TABLE 1

Baseline characteristics of the included randomised controlled trials (RCTs)

StudyStudy design, clinical setting, follow-upNWithdrawal (M/C)Mean (sd) age, years,
males, %		Inclusion diagnosisSputum at presentationTreatment regimen
Ansari et al. [42]RCT NR, inpatient, ≥7 days504/646.2 (10.7)
65.0%		Clinical AECOPD diagnosis with spirometric airflow obstructionNRNAC 1200 mg p.o. (twice daily), ≥7 days versus standard treatment
Aytemur et al. [53]RCT DB, inpatient, 6 months421/369 (8.8)
92.1%		AECOPD with previous spirometry confirmationIncreased volume (>50 mL·day−1)NAC 600 mg p.o. (three times daily), 30 days versus placebo
Bisetti et al. [52]RCT DB,
inpatient, 7 days		280/162.3 (NR)
67.9%		Clinical AECOPD diagnosis
Background: chronic bronchitis		MucopurulentErdosteine 600 mg p.o. (twice daily), 7 days versus placebo
Black et al. [54]RCT DB,
inpatient, 7 days		500/073.3 (8)
60.0%		AECOPD with spirometric airflow obstruction admitted for ≤24 hMostly increased volumeNAC 600 mg p.o. (twice daily), ≤7 days versus placebo
Brocard et al. [29]RCT DB,
NR, 10 days		95NRNRAcute infective exacerbation
Background: chronic bronchitis		NRNAC 600 mg p.o. (three times daily) 10 days versus placebo
El Hafiz et al. [55]RCT DB,
inpatient, >10 days		450/059 (7.5)
100%		AECOPD with airflow obstruction in spirometry
GOLD criteria fulfilment		NRNAC 600 mg p.o. (three times daily), NAC 1200 mg p.o. (three times daily), 10 days versus standard treatment
Galdi et al. [36]RCT DB,
inpatient, NR		412/475.8 (9.4)
34.1%		AECOPD requiring NIPPV
Previous diagnosis of COPD		NRNeb high molecular weight hyaluronan 0.3% 5 mL saline (twice daily) during NIPPV versus placebo
Jahnz-Rózyk et al. [37]RCT DB,
inpatient, NR		300/070.5 (6.9)
43.3%		Clinical AECOPD diagnosis
Background: chronic bronchitis		NRNeb ambroxol 30 mg (twice daily), up to clinical and spirometric improvement versus placebo
Langlands et al. [44]RCT DB,
inpatient, 20 days		313/1NR
81.5%		AECOPD based on MRC criteria
Background: chronic bronchitis		MucoidBromhexine 24 mg p.o. (three times daily), 14 days versus placebo
Li et al. [40]RCT NR,
inpatient, 10 days		606/468.1 (8.8)
62%		Chinese medicine syndrome of retention of phlegm and heat in Fei with airflow obstruction in spirometry
Onset ≤1 week		NRAmbroxol 30 mg i.v. (twice daily), 10 days versus standard treatment
Maesen et al. [30]RCT SB,
inpatient, 17 days		22NRNRInfective AECOPD
Background: chronic bronchitis		Increased purulenceBromhexine 72 mg (three times daily), 10 days versus placebo
Marchioni et al. [31]RCT DB,
NR, 11 days		2376/564.1 (10.7)
76.4%		Infective, clinical AECOPD
Background: chronic bronchitis		NRErdosteine 600 mg p.o. (twice daily), 7–10 days versus placebo
Mohanty et al. [50]RCT DB,
NR, NR		24040
total		NR,
NR		Clinical AECOPD diagnosis
Background: chronic bronchitis		NRErdosteine 600 mg p.o., NR versus placebo
Moretti et al. [48, 49]RCT SB, inpatient,
60 days		150/069.6 (5.6)
NR		Clinical AECOPD diagnosis
Hospitalisation ≤48 h from symptom onset		NRErdosteine 900 mg (three times daily), 10 days versus placebo
Moretti et al. [46, 56]RCT SB,
inpatient, 60 days		400/070.7 (5.8)
82.5%		Clinical AECOPD diagnosis with onset ≤24 hIncreased volume and purulenceErdosteine 900 mg p.o. (three times daily), 10 days versus standard treatment
Paganin et al. [32]RCT NR,
NR, >10 days		244 (total)61.5 (7.4)
79.2%		Infective, clinical AECOPD diagnosis with airflow limitationIncreased purulenceAmbroxol 90 mg p.o. (three times daily), 10 days versus standard treatment
Patel et al. [38]RCT SB,
inpatient, 30 days		709/061.2 (9.3)
49.2%		AECOPDNRNeb hypertonic saline 3.00% (every 6 h and as needed), 24 h versus neb normal saline 0.9%
Peralta et al. [33]RCT DB,
NR, 10 days		241 (total)60 (8.4)
NR		Infective, clinical AECOPD
Background: chronic bronchitis		Increased purulenceAmbroxol 90 mg p.o. (three times daily), 10 days versus standard treatment
Reichenberger et al. [34]RCT NR, NR, 21 days24NR66 (10)
66.7%		Infective clinical AECOPD
Background: chronic bronchitis		NRNAC 1200 mg (twice daily), 21 days versus standard treatment
Ren et al. [39]Q-RCT SB, inpatient, NR78080.8 (4.4)
62.8%		Clinical AECOPD diagnosis, according to the Respiratory Branch of the Chinese Medical AssociationNRInh NAC 600 mg (twice daily), NR versus inh normal saline (6 mL)
Ricevuti et al. [35]RCT DB,
NR, 8 days		30051.5 (NR)
46.7%		Infective, clinical AECOPD
Background: chronic bronchitis		Increased viscosity and volumeErythromycin-propionate-N-acetylcysteinate p.o. (three times daily), 7 days versus erythromycin stearate
Study
7171L01 [45]		RCT DB, NR,
30 days		71418.21/17NR
NR		Anthonisen's criteria for AECOPD and BCSS ≥5
ATS/ERS criteria for COPD (documentation ≤1 year)		NRN-Acetylcysteine 1200 mg, 600 mg p.o. (once), 10 days versus placebo
Zhang et al. [41]RCT NR,
NR, NR		80NRNR
NR		AECOPDNRAmbroxol 60 mg i.v. (twice daily), NR versus standard treatment
Zuin et al. [51]RCT DB,
outpatient, 10 days		1220.1/166.7 (12.4)
57.4%		Clinical AECOPD diagnosiNRNAC 600 mg p.o. (once and once placebo), 1200 mg p.o. (twice daily), 10 days versus placebo (twice daily)

AECOPD: acute exacerbation of chronic obstructive pulmonary disease; ATS: American Thoracic Society; BCSS: Breathlessness, Cough and Sputum Scale; C: control group; DB: double-blinded; ERS: European Respiratory Society; GOLD: Global Initiative for Chronic Obstructive Lung Disease; inh: inhaled; i.v.: intravenous; M: mucolytic group; MRC: Medical Research Council; N: number of patients; NAC: N-acetylcysteine; neb: nebulised; NIPPV: noninvasive positive pressure ventilation; NR: not reported; p.o.: per os; Q-RCT: quasi-randomised controlled trial; SB: single-blinded; sd: standard deviation.