Figures
- FIGURE 1
Flow diagram for the identification of the clinical studies included in the systematic review.
- FIGURE 2
a) Traffic light plot for assessment of the risk of bias of each included randomised controlled trial and b) weighted plot for the assessment of the overall risk of bias via the Cochrane Risk of Bias 2 tool (n=16 studies, from 16 records).
- FIGURE 3
The beneficial effect of long-acting muscarinic antagonists (LAMAs) against mucus hypersecretion in large and medium bronchi, and in small airways when using inhaler devices effective at delivering the drug into the small airway compartment. ACh: acetylcholine; LAMA: long-acting muscarinic antagonist; mAChRs: M3 muscarinic ACh receptors.
Tables
- TABLE 1
Main characteristics and results of the studies included in the systematic review
Study, year, reference clinicaltrials.gov identifier Study characteristics Treatment duration (weeks) Number of analysed patients Drugs, doses and regimen of administration# Inhaler device (brand) Patient characteristics Age (years) Male (%) Current smokers (%) Smoking history (pack-years) Post-bronchodilator FEV1 (% predicted) Outcome measurements of the impact on airway mucus Jadad score Main results Smith et al. 2019 [37] NCT02375724 Multicentre, phase IV, randomised, double-blind, PCB-controlled, parallel-group 8 269 ACL 400 μg twice daily versus PCB ACL: multidose DPI (Genuair/Pressair) Moderate COPD 62.0 60.2 64.0 NA 64.2 E-RS cough and sputum domain score and LCQ total score 2 ACL significantly improved cough and sputum production in symptomatic patients with moderate COPD compared to placebo Beier et al. 2017 [27] NCT01462929 Post hoc analysis of a multicentre, phase IIIB, randomised, double-blind, double-dummy, PCB- and active-controlled, parallel-group 6 277 ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB ACL: MDI (Genuair/Pressair); TIO: DPI (HandiHaler) Symptomatic moderate to severe COPD (FEV1 ≥30% and <80% of predicted; post- bronchodilator FEV1/FVC<0.7; E-RS in COPD baseline score ≥10 units) 62.1 64.1 54.1 41.0 54.6 E-RS cough and sputum domain score and in severity of early-morning cough and phlegm symptoms 5 ACL provided additional improvements compared to TIO in E-RS cough and sputum symptoms in patients with moderate to severe COPD Tagaya et al. 2016 [28] NA Open-label, non-controlled 8 22 TIO 18 μg once daily DPI (HandiHaler) COPD 67.0 81.8 0.0 NA 59.0 CASA-Q score, nasal clearance time, and level of mucin concentration in sputum NA TIO decreased symptoms associated with sputum in COPD patients Jones et al. 2016 [38] NCT01001494 (ATTAIN study) [46]; NCT01437397 (AUGMENT COPD I study) [47] Post hoc pooled analysis of two multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group studies 24 1161 ACL 400 μg twice daily versus PCB MDI (Genuair/Pressair); Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) 63.2 60.6 51.9 47.1 54.4 E-RS cough and sputum domain score ATTAIN: 5; AUGMENT COPD I: 5 ACL significantly improved E-RS cough and sputum symptoms regardless of the patients’ level of symptoms at baseline Lange et al. 2016 [39] NA Multicentre, real-life, prospective, non-interventional ≃24 874 ACL 400 μg twice daily (either as initial therapy, switch of treatment or as add-on therapy) MDI (Genuair) COPD (NA) 69.3 46.0 36.0 NA 54.9 CAT score for cough and mucus NA ACL was associated with a significant improvement in CAT score for cough and mucus, an effect more pronounced in the LAMA naïve group McGarvey et al. 2016 [29] NCT00891462 (ACCORD COPD I study) [42]; NCT01001494 (ATTAIN study) [46]; NCT01462929 [31] Post hoc analysis of three multicentre, phase III, randomised, double-blind, PCB-controlled (and active-controlled for NCT01462929), parallel-group studies 12 (ACCORD COPD I study), 24 (ATTAIN study), 6 NCT01462929 1792 ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB ACL: multidose DPI (Genuair/Pressair); TIO: DPI (HandiHaler) Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) 63.1 62.5 51.4 45.3 55.6 E-RS cough and sputum domain score and frequency/severity of morning and night-time cough and sputum symptoms ACCORD COPD I: 5; ATTAIN: 5; NCT01462929: 5 ACL improved cough and sputum expectoration compared to PCB in stable COPD Bateman et al. 2015 [40] NCT01462942 (ACLIFORM-COPD study) [43]; NCT01437397 (AUGMENT COPD I study) [47] Post hoc pooled analysis of two multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group studies 24 2680 ACL/FOR 400/12 μg twice daily versus ACL 400 μg twice daily versus FOR 12 μg twice daily versus PCB Multidose DPI (Genuair/Pressair) Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) 63.6 60.0 49.3 ≥10.0 53.6 E-RS cough and sputum domain score and in early-morning and night-time cough and difficulty in bringing up phlegm symptoms score ACLIFORM-COPD: 5; AUGMENT COPD I: 5 ACL/FOR significantly improved the early-morning and night-time difficulty in bringing up phlegm compared to PCB in patients with moderate to severe COPD Marth et al. 2015 [41] NA Multicentre, real-life, prospective, non-interventional ≃12 795 ACL 400 μg twice daily (either as initial therapy, switch of treatment or as add-on therapy) Multidose DPI (Eklira Genuair) COPD (NA) 63.2 56.0 44.0 ≥10.0 NA CAT score for cough and phlegm NA ACL significantly reduced the CAT score for phlegm and cough in COPD patients D’Urzo et al. 2014 [30] NCT01005901 (GLOW1) [44]; NCT00929110 (GLOW2) [45] Post hoc pooled analysis of two phase III, multicentre, randomised, double-blind (open-label TIO in GLOW2), PCB-controlled, active-controlled (only GLOW2), parallel-group studies 26 (GLOW1); 52 (GLOW2) 1854 GLY 50 μg once daily versus PCB (GLOW1);
GLY 50 μg once daily versus PCB versus open-label TIO 18 μg once daily (GLOW2)GLY: DPI (Breezhaler); TIO: DPI (HandiHaler) Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) 63.8 71.0 40.5 47.3 55.4 Symptom score for cough, sputum production, and sputum colour GLOW1: 3;
GLOW2: 3TIO and GLY significantly improved the sputum production in moderate to severe COPD patients Beier et al. 2013 [31] NCT01462929 Multicentre, phase IIIB, randomised, double-blind, double-dummy, PCB- and active-controlled, parallel-group 6 414 ACL 400 μg twice daily versus TIO 18 μg once daily versus PCB ACL: MDI (Genuair/Pressair); TIO: DPI (HandiHaler) Moderate to severe COPD (FEV1 ≥30% and <80% of predicted; post- bronchodilator FEV1/FVC<0.7) 62.3 65.5 53.6 42.0 55.8 E-RS cough and sputum domain score 5 Improvement in E-RS cough and sputum symptoms were significantly greater for ACL and TIO compared to PCB Kerwin et al. 2012 [42] (ACCORD COPD I study) NCT00891462 Multicentre, phase III, randomised, double-blind, PCB-controlled, parallel-group 12 560 ACL 200 μg twice daily versus ACL 400 μg twice daily versus PCB ACL: MDI (Genuair/Pressair) Moderate to severe stable COPD (FEV1 ≥30% and <80% of predicted; post-bronchodilator FEV1/FVC<0.7) 64.3 53.0 44.8 54.3 47.2 Frequency of night-time cough and sputum production, and severity of cough 5 Treatment of moderate-to-severe COPD patients with ACL was associated with significant improvements in night-time symptoms due to cough and sputum production, and severity of cough, compared to PCB Welte et al. 2009 [32] NCT00496470 Multicentre, phase IV, randomised, double-blind, parallel-group 24 660 TIO 18 μg once daily+BUD/FOR 320/9 μg twice daily versus TIO 18 μg once daily+PCB TIO: DPI (HandiHaler); BUD/FOR: DPI (Turbuhaler) COPD (pre- bronchodilator FEV1 ≤50% of predicted; history of exacerbations requiring systemic steroids and/or antibiotics) 62.5 75.0 NA 37.0 37.9 Symptom score for cough 4 In patients with COPD TIO added to BUD/FOR FDC provided rapid and sustained improvement in symptom score for cough compared to TIO alone Powrie et al. 2007 [33] NCT00405236 Single-centre, randomised, double-blind, PCB-controlled, parallel-group 52 142 TIO 18 μg once daily versus PCB TIO: DPI (HandiHaler) COPD (FEV1 <80% of predicted and FEV1/FVC<0.7) 66.4 62.9 58.5 55.2 50.1 Sputum reduction 3 Administration of TIO was significantly associated with a subjective decrease in sputum production compared to COPD patients treated with PCB Hasani et al. 2004 [34] NA Single-centre, randomised, double-blind, PCB-controlled, parallel-group 3 34 TIO 18 μg once daily versus PCB TIO: DPI (HandiHaler) COPD (FEV1 ≥30% and ≤65% of predicted; post- bronchodilator FEV1/FVC≤0.7) 66.0 79.4 58.8 52.0 44.0 Number of coughs 4 Cough frequency was reduced with TIO compared to PCB during 6 h post administration Casaburi et al. 2002 [35] NA Two multicentre, randomised, double-blind, PCB-controlled studies 52 921 TIO 18 μg once daily versus PCB TIO: DPI (HandiHaler) COPD (FEV1 ≤65% of predicted; post- bronchodilator FEV1/FVC≤0.7) 65.2 65.0 NA 61.0 38.6 Symptom score for cough 5 In patients with stable COPD, TIO did not modulate the symptom score for cough after 52 weeks of treatment compared to PCB Casaburi et al. 2000 [36] NA Multicentre, randomised, double-blind, PCB-controlled, parallel-group 13 470 TIO 18 μg once daily versus PCB TIO: DPI (HandiHaler) COPD (FEV1 ≤65% of predicted; post- bronchodilator FEV1/FVC<0.7) 65.2 65.3 NA 62.9 39.0 Symptom score for cough 4 In patients with stable COPD, TIO reduced the symptom score for cough after 8 days of treatment but not at week 13, compared to PCB #: All studies analysed long-acting muscarinic antagonists (LAMAs) administered through oral inhalation. ACL: aclidinium bromide; BUD: budesonide; CASA-Q: Cough and Sputum Assessment - Questionnaire; CAT: COPD Assessment Test; DPI: dry powder inhaler; E-RS: Exacerbations of Chronic Pulmonary Disease Tool–Respiratory Symptoms; FDC: fixed-dose combination; FEV1: forced expiratory volume in 1 s; FOR: formoterol; FVC: forced vital capacity; GLY: glycopyrronium; LCQ: Leicester Cough Questionnaire; MDI: metered-dose inhaler; NA: not available; PCB: placebo; pMDI: pressurised metered dose inhaler; TIO: tiotropium bromide.
Supplementary Material
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PRISMA checklist ERR-0196-2021.SUPPLEMENT
Vol 31 Issue 164
Table of Contents
The impact of long-acting muscarinic antagonists on mucus hypersecretion and cough in chronic obstructive pulmonary disease: a systematic review
