Chronic obstructive pulmonary disease (COPD) is an inflammatory condition characterized by irreversible airflow obstruction. It is caused by exposure to noxious particles or gases, with exposure to cigarette smoke the most common cause. Several classes of drugs can be prescribed: short and long-acting beta2 (β2) agonist, short and long-acting antimuscarinic, inhaled corticosteroids and phosphodiesterase-4 inhibitors. We are conducting a class review of all long-acting beta2 (β2) agonist (LABA) drugs and indacaterol is the first of this series. (see Indacaterol) All drugs to treat COPD are licensed by regulatory authorities based on short duration randomized trials showing an improvement in a surrogate marker, Forced Expiratory Volume in 1 second (FEV1). This surrogate marker does not reflect the main concerns of patients with COPD, preventing acute moderate to severe exacerbations, improving quality of life and reducing symptoms such as shortness of breath.1 The approved doses, brand names and year of approval by three regulatory agencies are shown in Table 1.
|Regulatory Agency||Brand Name||Approved Dose||Year Approved|
|European Medicines Agency (EMA)||Onbrez Breezhaler||150 and 300 μg daily||2009|
|US Food and Drug Administration (FDA)||Arcapta Neohaler||75 μg daily||2011|
|Health Canada||Onbrez Breezhaler||75 μg daily||2012|
To determine the clinical efficacy of inhaled indacaterol as compared to placebo in adult patients with COPD.
Type of studies: Randomized placebo controlled parallel group clinical trials.
Type of participants: Adult patients with clinical diagnosis of COPD.
Type of interventions: Indacaterol at various doses (once or twice daily) compared to placebo control group.
Type of outcomes: Total mortality; total serious adverse events; number of patients with one or more acute moderate to severe exacerbation; quality of life measured by Saint George Respiratory Questionnaire (SGRQ) total score; time to first exacerbation; improvement in symptoms such as dyspnea measured by Transient Dyspnea Index (TDI score), need for rescue medications; total adverse events; total withdrawals, withdrawals due to adverse effects and COPD related health care utilization.
We searched for all relevant RCT reports in Medline, Embase, CENTRAL, EBSCO CINAHL, ClinicalTrials.gov, Drugs@FDA, EMA public assessment reports and manufacturer’s website.
Data Collection and Analysis
Two independent reviewers selected the studies and extracted the data. We conducted a meta-analysis to compare the incidence of outcomes between indacaterol and placebo and presented the results as relative risks (RR) with 95% confidence intervals (CI) for dichotomous outcomes and as weighted mean difference (WMD) for continuous outcomes. We assessed risk of bias for each trial using the Cochrane risk of bias tool.
We identified 12 RCTs2-11 that met the inclusion criteria, comprising 6,947 adult patients with stable COPD. Patients with concurrent respiratory disease, including asthma, were excluded. Patients could continue using inhaled corticosteroids at the stable dose throughout the studies. Oral corticosteroids were not allowed. Salbutamol/albuterol could be used for rescue as needed. No other bronchodilators were permitted. Duration of trials ranged from 12 weeks (8 trials) to 26 weeks (3 trials). Only one trial was 52 weeks in duration. Indacaterol doses included 27.5 µg twice daily, 75 µg, 150 µg, 300 µg and 600 µg once daily. Four RCTs included more than one dose of indacaterol.3-6 Subgroup analysis showed no significant differences between various doses so results for all outcomes are presented as overall RR or WMD with 95% CI (see Table 2). The number of patients with one or more acute moderate to severe exacerbations, time to first exacerbation and COPD-related health care utilization outcomes were not reported in any study.
|Outcome in Published Literature||Participants (Studies)||RR or WMD (95% CI)|
|Mortality||6,913 (11)||0.47 (0.21 to 1.07)|
|Total serious adverse events||6,908 (11)||1.00 (0.83 to 1.19)|
|Participants experiencing one or more exacerbation of any severity||3,255 (3)||0.84 (0.74 to 0.95)|
|WMD in SGRQ score||
-3.46 (-4.31 to -2.62)
|≥ 4-point difference in SGRQ score||1,566 (3)||1.28 (1.15 to 1.42)|
|Need for rescue medication||2,192 (5)||-0.80 (-0.99 to -0.61)|
|Total adverse events||6,905 (11)||1.04 (0.99 to 1.09)|
|Withdrawals due to adverse effects||6,911 (11)||0.80 (0.66 to 0.98)|
|Total withdrawals||6,912 (11)||0.66 (0.60 to 0.73)|
See also: Indacaterol
Risk of bias
Dose ranging efficacy
No significant difference in any outcome measure was noted between the lowest dose 27.5 µg bid and 600 µg once daily. Comparing two different doses within the same study showed no significant difference in any outcome measure between 300 and 150 µg or 600 and 300 µg dose.
A systematic review of all available evidence showed no statistically significant difference in mortality, total serious adverse events and total adverse events (see Indacaterol). Lower incidence of total withdrawals and withdrawal due to adverse effects in the indacaterol group was due to perceived lack of efficacy in the placebo group, which likely reflects loss of blinding. For all other outcomes, the small but statistically significant reduction in patients experiencing one or more exacerbation of any severity; quality of life scores and reduced need for rescue medication are based on a subset of total randomised patients and represents very low quality evidence which may not be real, or at best is an exaggeration of the real benefit.13
Other systematic reviews
In contrast to our review (see Indacaterol), a Cochrane review14 published in 2015 judged the overall risk of bias to be minimal and thus they were more positive about the efficacy of indacaterol. A non-Cochrane systematic review15 rated the overall quality of included studies as mediocre with poor reporting of methodological details. They concluded that indacaterol at dosage < 150 µg improved FEV1, SGRQ and TDI score in patients with moderate to severe stable COPD, but at a dose of 300 µg indacaterol did not prevent exacerbations at 1 year.
- The only single product dose of inhaled indacaterol approved in Canada is 75 µg.
- Doses of indacaterol higher than 75 µg were not significantly different in any clinically meaningful outcome measure as compared to lower doses.
- There are no proven clinically meaningful benefits in terms of reduction in mortality or total serious adverse events for indacaterol in patients with COPD.
- Because the overall evidence is graded as of very low quality, it is unclear whether indacaterol causes a clinically meaningful reduction in acute exacerbations, improvement in quality of life, dyspnea or reduced need for rescue medications.
- For any new class of drugs for COPD, evidence of a reduction in clinically relevant outcomes should be required for licensing.
- McDonagh M, Holmes R, Blazina I, et al. Drugs to Treat Asthma and Chronic Obstructive Pulmonary Disease (COPD). Final Update 1 Report prepared by the Pacific Northwest Evidence-based Practice Center for the Drug Effectiveness Review Project. Oregon Health & Science University, Portland, Oregon, June 2016. http://www.hca.wa.gov/assets/program/asthma-copd-update1-2016.pdf
- Gotfried MH, Kerwin EM, Lawrence D, et al. Efficacy of indacaterol 75 mug once-daily on dyspnea and health status: results of two double-blind, placebo-controlled 12-week studies. COPD 2012;9(6):629-36. DOI: 10.3109/15412555.2012.729623
- 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. DOI: 10.1136/thx.2009.125435
- Donahue JF, Fogarty C, Lotvall 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. DOI: 10.1164/rccm.200910-1500OC
- Kinoshita M, Lee SH, Hang LW, et al. Efficacy and safety of indacaterol 150 and 300 micro g in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week placebo controlled study. Respirology 2012;17(2):379-89. DOI: 10.1111/j.1440-1843.2011.02107.x
- 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. DOI: 10.1111/resp.12211
- 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. DOI: 10.1183/09031936.00200212
- Feldman G, Siler T, Prasad N, et al. Efficacy and safety of indacaterol 150 microg once-daily in COPD: a double-blind, randomised, 12-week study. BMC polm med 2010;10:11. DOI: 10.1186/1471-2466-10-11
- 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. DOI: 10.1183/09031936.00045810
- Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015; 192(9):1068-79. DOI: 10.1164/rccm.201505-1048OC
- Mroz R.M, Minarowski L, Chyczewska E. Indacaterol add-on therapy improves lung function, exercise capacity and life quality of COPD patients. Adv Exp Med Biol 2013;756:23-8. DOI: 10.1007/978-94-007-4549-0_4
- Higgins JPT, Altman DG, Sterne JAC, (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
- Schünemann HJ, Oxman AD, Vist GE, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
- Geake JB, Dabscheck EJ, Wood-Baker R, Cates CJ. Indacaterol, a once-daily beta2-agonist, versus twice-daily beta2-agonists or placebo for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD010139. DOI: 10.1002/14651858.CD010139.pub2
- Chung VC, Ma PH, Hui DS, et al. Indacaterol for chronic obstructive pulmonary disease: systematic review and meta-analysis. PLoS ONE 2013;8(8): e70784. DOI: 10.1371/journal.pone.0070784