Figures
- FIGURE 1
Risk of bias table. D1: bias arising from the randomization process; D2: bias due to deviations from the intended intervention; D3: bias due to missing outcome data; D4: bias in measurement of the outcome; D5: bias in selection of the reported result.
- FIGURE 2
Forest plots depicting the overall effect estimates for the following outcomes upon treatment completion: a) treatment success; b) overall symptom scores; c) absence of breathlessness; d) absence of cough; e) ease of expectoration. M–H: Mantel–Haenszel method; SMD: standardised mean difference.
Tables
- TABLE 1
Baseline characteristics of the included randomised controlled trials (RCTs)
Study Study design, clinical setting, follow-up N Withdrawal (M/C) Mean (sd) age, years,
males, %Inclusion diagnosis Sputum at presentation Treatment regimen Ansari et al. [42] RCT NR, inpatient, ≥7 days 50 4/6 46.2 (10.7)
65.0%Clinical AECOPD diagnosis with spirometric airflow obstruction NR NAC 1200 mg p.o. (twice daily), ≥7 days versus standard treatment Aytemur et al. [53] RCT DB, inpatient, 6 months 42 1/3 69 (8.8)
92.1%AECOPD with previous spirometry confirmation Increased 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 days28 0/1 62.3 (NR)
67.9%Clinical AECOPD diagnosis
Background: chronic bronchitisMucopurulent Erdosteine 600 mg p.o. (twice daily), 7 days versus placebo Black et al. [54] RCT DB,
inpatient, 7 days50 0/0 73.3 (8)
60.0%AECOPD with spirometric airflow obstruction admitted for ≤24 h Mostly increased volume NAC 600 mg p.o. (twice daily), ≤7 days versus placebo Brocard et al. [29] RCT DB,
NR, 10 days95 NR NR Acute infective exacerbation
Background: chronic bronchitisNR NAC 600 mg p.o. (three times daily) 10 days versus placebo El Hafiz et al. [55] RCT DB,
inpatient, >10 days45 0/0 59 (7.5)
100%AECOPD with airflow obstruction in spirometry
GOLD criteria fulfilmentNR NAC 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, NR41 2/4 75.8 (9.4)
34.1%AECOPD requiring NIPPV
Previous diagnosis of COPDNR Neb high molecular weight hyaluronan 0.3% 5 mL saline (twice daily) during NIPPV versus placebo Jahnz-Rózyk et al. [37] RCT DB,
inpatient, NR30 0/0 70.5 (6.9)
43.3%Clinical AECOPD diagnosis
Background: chronic bronchitisNR Neb ambroxol 30 mg (twice daily), up to clinical and spirometric improvement versus placebo Langlands et al. [44] RCT DB,
inpatient, 20 days31 3/1 NR
81.5%AECOPD based on MRC criteria
Background: chronic bronchitisMucoid Bromhexine 24 mg p.o. (three times daily), 14 days versus placebo Li et al. [40] RCT NR,
inpatient, 10 days60 6/4 68.1 (8.8)
62%Chinese medicine syndrome of retention of phlegm and heat in Fei with airflow obstruction in spirometry
Onset ≤1 weekNR Ambroxol 30 mg i.v. (twice daily), 10 days versus standard treatment Maesen et al. [30] RCT SB,
inpatient, 17 days22 NR NR Infective AECOPD
Background: chronic bronchitisIncreased purulence Bromhexine 72 mg (three times daily), 10 days versus placebo Marchioni et al. [31] RCT DB,
NR, 11 days237 6/5 64.1 (10.7)
76.4%Infective, clinical AECOPD
Background: chronic bronchitisNR Erdosteine 600 mg p.o. (twice daily), 7–10 days versus placebo Mohanty et al. [50] RCT DB,
NR, NR240 40
totalNR,
NRClinical AECOPD diagnosis
Background: chronic bronchitisNR Erdosteine 600 mg p.o., NR versus placebo Moretti et al. [48, 49] RCT SB, inpatient,
60 days15 0/0 69.6 (5.6)
NRClinical AECOPD diagnosis
Hospitalisation ≤48 h from symptom onsetNR Erdosteine 900 mg (three times daily), 10 days versus placebo Moretti et al. [46, 56] RCT SB,
inpatient, 60 days40 0/0 70.7 (5.8)
82.5%Clinical AECOPD diagnosis with onset ≤24 h Increased volume and purulence Erdosteine 900 mg p.o. (three times daily), 10 days versus standard treatment Paganin et al. [32] RCT NR,
NR, >10 days24 4 (total) 61.5 (7.4)
79.2%Infective, clinical AECOPD diagnosis with airflow limitation Increased purulence Ambroxol 90 mg p.o. (three times daily), 10 days versus standard treatment Patel et al. [38] RCT SB,
inpatient, 30 days70 9/0 61.2 (9.3)
49.2%AECOPD NR Neb 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 days24 1 (total) 60 (8.4)
NRInfective, clinical AECOPD
Background: chronic bronchitisIncreased purulence Ambroxol 90 mg p.o. (three times daily), 10 days versus standard treatment Reichenberger et al. [34] RCT NR, NR, 21 days 24 NR 66 (10)
66.7%Infective clinical AECOPD
Background: chronic bronchitisNR NAC 1200 mg (twice daily), 21 days versus standard treatment Ren et al. [39] Q-RCT SB, inpatient, NR 78 0 80.8 (4.4)
62.8%Clinical AECOPD diagnosis, according to the Respiratory Branch of the Chinese Medical Association NR Inh NAC 600 mg (twice daily), NR versus inh normal saline (6 mL) Ricevuti et al. [35] RCT DB,
NR, 8 days30 0 51.5 (NR)
46.7%Infective, clinical AECOPD
Background: chronic bronchitisIncreased viscosity and volume Erythromycin-propionate-N-acetylcysteinate p.o. (three times daily), 7 days versus erythromycin stearate Study
7171L01 [45]RCT DB, NR,
30 days714 18.21/17 NR
NRAnthonisen's criteria for AECOPD and BCSS ≥5
ATS/ERS criteria for COPD (documentation ≤1 year)NR N-Acetylcysteine 1200 mg, 600 mg p.o. (once), 10 days versus placebo Zhang et al. [41] RCT NR,
NR, NR80 NR NR
NRAECOPD NR Ambroxol 60 mg i.v. (twice daily), NR versus standard treatment Zuin et al. [51] RCT DB,
outpatient, 10 days122 0.1/1 66.7 (12.4)
57.4%Clinical AECOPD diagnosi NR NAC 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.
- TABLE 2
Grading of Recommendation, Assessment, Development and Evaluation (GRADE) evidence profile
Outcome Measure n (N) Effect estimates Certainty Benefit Risk of bias Inconsistency Indirectness Imprecision Other Overall certainty Treatment success N 4 (383) Relative risk 1.37 (1.08–1.73), I2=63% Serious# Not serious Not serious Not serious Not serious Moderate Yes Overall symptom score Post-treatment scores 3 (316) SMD 0.86 (0.63–1.09), I2=0% Serious# Not serious Not serious Not serious Not serious Moderate Yes Change from pre-treatment 1 (50) SMD 0.80 (0.22–1.38) Serious# Not serious Not serious Not serious Not serious N with improvement 1 (200) Relative risk 1.18 (1.07–1.31) Serious# Not serious Not serious Not serious Not serious Dyspnoea cough attacks 1 (30) MD −1.40 (−3.51–0.71) Serious# Not serious Not serious Serious¶ Not serious Breathlessness N with absence 2 (276) Relative risk 1.36 (0.55–3.38), I2=85% Serious# Serious+ Not serious Serious¶ Not serious Very low No Change from pre-treatment in Borg's scale 1 (59) MD 0.40 (−0.55–1.35) Serious# Not serious Not serious Serious¶ Not serious N with improvement 1 (27) Relative risk 1.08 (0.69–1.68) Serious# Not serious Not serious Serious¶ Not serious N with dyspnoea at rest 1 (40) Relative risk 0.18 (0.01–3.56) Serious# Not serious Not serious Serious¶ Not serious Cough N with absence 2 (276) Relative risk 1.93 (1.15–3.23), I2=29% Serious# Not serious Not serious Not serious Not serious Moderate Yes N with improvement in frequency/in intensity 1 (122) Relative risk 1.40 (0.88–2.22)/Relative risk 2.06 (1.23–3.43) Serious# Not serious Not serious Serious¶ Not serious Ease of expectoration N with improvement 2 (149) Relative risk 2.94 (1.68–5.12), I2=0% Serious# Not serious Not serious Not serious Not serious Moderate Yes N with absence 1 (226) Relative risk 3.71 (1.87–7.38) Serious# Not serious Not serious Not serious Not serious Health-related quality of life Change from pre-treatment 1 (78) MD 0.7 (0.6–0.8) Serious# Not serious Not serious Serious¶ Not serious Low Yes Length of hospital stay Mean duration in days 3 (114) MD −1.04 (−4.66–2.58), I2=76% Serious# Not serious Not serious Serious¶ Not serious Low No ICU admission and ventilation N 2 (83) Relative risk 0.36 (0.06–2.17), I2=0% Serious# Not serious Not serious Serious¶ Not serious Low No Future exacerbations N with re-exacerbation at day 30 2 (55) Relative risk 0.08 (0.00–1.28) Serious# Not serious Not serious Serious¶ Not serious Very Low Yes HR, 2 months follow-up 1 (40) HR 0.169 (0.033–0.875) Serious# Not serious Not serious Serious¶ Not serious Time to first (days), 6 months follow-up 1 (38) MD 27.70 (−4.55–59.95) Serious# Not serious Not serious Serious¶ Not serious Mortality N 4 (173) Relative risk 0.73 (0.11–4.90), I2=16% Serious# Not serious Not serious Serious¶ Not serious Low No SAEs N 2 (109) No SAEs were observed Serious# Not serious Not serious Serious¶ Not serious Low No risk #All studies included in this systematic review were deemed to be of at least some concern of methodological bias. ¶Broad confidence intervals and/or insufficient overall study population. +Marchioni et al. [31] reported significant improvement in dyspnoea; however, significance was lost in a meta-analysis that included a second, smaller randomised controlled trial. n: Number of trials; N: number of patients; HR: hazard ratio; ICU: intensive care unit; MD: mean difference; SAE: serious adverse event; SMD: standardised mean difference.
- TABLE 3
Summary of evidence per mucolytic, per outcome
Mucolytics/outcomes N-Acetylcysteine Ambroxol Erdosteine Bromhexine Hypertonic saline Hyaluronan Treatment success NA N=50 (+) N with resolution or significant improvement of symptoms and laboratory findings [40]
N=80 (+) N with clinical efficacy [41]N=27 (+) N with clinical judgement of effectiveness [52]
N=226 (+) N with resolution of symptoms [31]NA NA NA Patient reported NA 30 (−) Number of dyspnoea and cough attacks [37] 226 (+) Global clinical assessment score [31]
200 (+) N with improvement [50]NA NA NA Overall symptom score NA 50 (+) Chinese medical symptom score, mean change [40] 55 (+) Breathlessness–sputum–cough scale [46, 48] NA NA Breathlessness 40 (−) N per severity [42]
88 (−) Likert score 0–7, nonvalidated [53, 54]50 (−) Chinese medical symptom score [40] 226 (+) Nonvalidated score 0–3 [31]
N with absence [31]27 (−) N with improvement [44] 59 (−) Modified Borg scale [38] NA Cough 38 (−) Nonvalidated score 0–7 [53]
95 (+) Nonvalidated score 0–3 [29]
122 (+) N with improvement in intensity [51]50 (+) N with severe cough affecting sleep, Chinese medical symptom score [40]
23 (−) Nonvalidated score 0–3 [33]253 (+) Nonvalidated score 0–3 [31, 52]
226 (+) N with absence [31] (same study as above)NA NA NA Ease of expectoration 38 (−) Nonvalidated score 0–7 [53]
122 (+) N with improvement [51]50 (−) Chinese medical symptom score [40]
23 (+) Nonvalidated score 0–3 [33]253 (+) Nonvalidated score 0–3 [31, 52]
226 (+) N with absence [31] (same study as above)27 (−) N with improvement [44] NA NA Sputum viscosity 30 (+) Nonvalidated score 0–3 [35] NA 27 (+) Centipoises, mean % change, compared to pre-treatment [52]
226 (+) Nonvalidated score 0–3 [31]
N with fluid saliva [31]27 (−) Centipoises and arbitrary units [44] NA NA Health-related quality of life 78 (+) Clinical COPD questionnaire, mean change [39] Hospitalisation duration 166 (−) [39, 53, 54] NA 52 (−) [46, 47] NA NA 36 (+) [36] Indication for higher level of care 42 (−) N with ICU admission and intubation [53] NA NA NA NA 41 (−) N needing invasive ventilation [36] Future exacerbations 38 (−) Rate by 6 months [53]
Time to first by 6 months [53]NA 40 (+) N by day 30 [46]
Hazard ratio by day 60 [46]
15 (−) Rate by day 30 [49]
(+) Rate by day 60 [49]NA NA NA Mortality 42 (−) N [53] NA NA 31 (−) N [44] 59 (−) N up to 30 days [43] 41 (−) N [36] Serious adverse events 50 (−) None [54] NA NA NA 59 (−) None [43] NA Various measurement instruments were used for assessing some of the outcomes. Results are pooled per instrument and for each instrument we present the overall population in which it was tested and whether there was evidence (+) or no evidence (−) of a beneficial effect with mucolytics. ICU: intensive care unit; N: number of participants; NA: not assessed in any trial.
Supplementary Material
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Supplementary material ERR-0141-2022.SUPPLEMENT
Vol 32 Issue 167
Table of Contents
Mucolytics for acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis
