Impact of Mucolytic Agents on COPD Exacerbations: A Pair-wise and Network Meta-analysis

Figures & data

Figure 1. PRISMA flow diagram for the identification of studies included in the meta-analysis concerning the impact of mucolytic agents on COPD exacerbations (A). Diagram displaying the network of the five arms involved in the Bayesian analysis. The links between nodes indicate the direct comparisons between pairs of treatments. The numbers shown along the link lines indicate the number of COPD patients comparing pairs of treatments head-to-head (B).

Table 1. Patient demographics, baseline and study characteristics.

Study, year and reference	Trial Number Identifier	Study characteristics	Study duration (weeks)	Analysed patients	Drugs and daily doses	Exacerbation rates (treatment/placebo)	Disease characteristics	Age (years)	Male (%)	Current smokers (%)	Smoking history (pack-years)	Post-bronchodilator FEV^1 (% predicted)	Jadad score
Zheng et al. 2014 (42)	ChiCTR-TRC-09000460	Multicentre, prospective, randomized, double-blind, placebo-controlled, parallel groups	52	964	N-acetylcysteine, 1200 mg	0.26/0.33	COPD, GOLD II-IV	66.3	81.9	17.8	36.2	48.9	4
Tse et al. 2013 (43)	NCT01136239	Double-blind, randomized placebo-controlled	52	108	N-acetylcysteine, 1200 mg	0.24/0.43	COPD, GOLD I-IV	70.9	93.3	23.3	NA	59.6	4
Schermer et al. 2009 (44)	NA	Double-blind, randomized, double dummy, placebo-controlled	156	108	N-acetylcysteine, 600 mg	0.15/0.14	COPD, GOLD I-IV	59.4	72.9	53.6	27.3	69.8	4
Zheng et al. 2008 (48)	UMIN-CRT C000000233	Multicentre, randomized, double-blind, placebo-controlled, parallel-group	52	707	Carbocysteine, 1500 mg	0.23/0.31	COPD, GOLD II-IV	65.2	78.5	74.5 (ever smokers)	NA	44.5	5
Bachh et al. 2007 (46)	NA	Single-blind, randomized, placebo-controlled study	16	100	N-acetylcysteine, 600 mg	0.56/0.83	COPD, GOLD II-III	61.4	78.0	NA	44.1	51.7	1
Tatsumi et al. 2007 (49)	NA	Multicenter, randomized, parallel-group	52	142	Carbocysteine, 1500 mg	0.07/0.25	COPD, FEV^1 < 70%	70.2	91.5	NA	NA	<70	1
Yasuda et al. 2006 (50)	NA	Randomized, double-blind, controlled trial	52	156	Carbocysteine, 1500 mg	0.13/0.35	COPD, GOLD I-III	72.7	85.3	NA	44.3	61.5	3
Decramer et al. 2005 (45)	NA	Double-blind, randomized, placebo-controlled, parallel groups	156	354	N-acetylcysteine, 600 mg	0.31/0.33	COPD, GOLD II-III	62.0	77.0	44.0	NA	57.0	4
Moretti et al. 2004 (51)	NA	Multicentre, randomized, double-blind, placebo-controlled, parallel-group	32	124	Erdosteine, 600 mg	0.35/0.52	COPD, FEV^1 < 70%	67.5	79.9	32.9	>20	59.2	3
Malerba et al. 2004 (52)	NA	Multicentre, randomized, double-blind, placebo-controlled, parallel-group	52	234	Ambroxol, 150 mg	0.11/0.12	COPD, FEV^1 ≥ 60%, <80%	60.6	72.6	32.9	NA	<80	3
Pela et al. 1999 (47)	NA	Open, randomized, controlled	24	167	N-acetylcysteine, 600 mg	0.48/0.84	COPD, FEV^1 < 70%	66.0	75.7	24.0	NA	58.1	2

NA, not available.

Table 2. Summary of the risk of bias for each included study assessed via the Cochrane Collaboration's tool (18).

	Selection	Performance	Detection	Attrition	Reporting
Zheng et al. 2014 (42)	+	+	+	−	+
Tse et al. 2013 (43)	?	+	+	?	+
Schermer et al. 2009 (44)	+	+	+	−	+
Zheng et al. 2008 (48)	+	+	+	?	+
Bachh et al. 2007 (46)	?	−	−	+	+
Tatsumi et al. 2007 (49)	+	−	+	−	+
Yasuda et al. 2006 (50)	+	+	−	+	+
Decramer et al. 2005 (45)	+	+	+	−	+
Moretti et al. 2004 (51)	?	+	+	−	+
Malerba et al. 2004 (52)	?	+	+	?	+
Pela et al. 1999 (47)	?	−	−	?	+

Table 3. Definition of COPD exacerbations as reported by studies included in the meta-analysis.

Study, year and reference	Definition of COPD exacerbation
Zheng et al. 2014 (42)	‘At least a 2 day persistence of two (type II moderate) or all three (type III, severe) major symptoms (worsening dyspnoea, increase in sputum purulence or volume), or of any one major symptom plus at least one minor symptom (type I, mild) (upper airway infection, unexplained fever, and increased wheezing).”
Tse et al. 2013 (43)	“Two of the following three symptoms: increase in shortness of breath, volume, or purulence of sputum.”
Schermer et al. 2009 (44)	“An episode with one or more subsequent unscheduled contacts with either a general practitioner or a chest physician due to worsening of respiratory symptoms.”
Zheng et al. 2008 (48)	“At least 2-day persistence of at least two major symptoms (worsening dyspnoea and an increase in sputum purulence, volume, or both), or of any single major symptom plus more than one minor symptom (upper airway infection, unexplained fever, and increased wheezing).”
Bachh et al. 2007 (46)	“Increased dyspnea and/or cough associated with a change in quality and quantity of sputum, which led the patient to seek medical attention and lasting for > 3 days.”
Tatsumi et al. 2007 (49)	“Changes in the following symptoms from their stable condition according to the Anthonisen criteria: dyspnea, sputum purulence, sputum volume, cold, wheeze, cough, fever, and change in respiratory rate or heart rate of 20%.”
Yasuda et al. 2006 (50)	“An acute and sustained worsening of COPD symptoms requiring changes to regular treatment, as previously described.”
Decramer et al. 2005 (45)	“Increase in dyspnoea, cough, or both associated with a change in quality and quantity of sputum, which led the patient to seek medical attention and which lasted for at least 3 days.”
Moretti et al. 2004 (51)	“New episodes of acute disease with muco-purulent or purulent sputum, cough and at least two of the following symptoms: general malaise, fever > 38°C, breathlessness, difficulty in expectoration and leukocytosis. The same definition was used for exacerbations occurring before and during the trial.”
Malerba et al. 2004 (52)	“A concomitance of purulent mucus plus at least one of the following: fever ≥ 38°C, general malaise, dyspnea, difficult expectoration, or leukocytosis (leukocytes count above upper normal value at a clinically significant degree and when previously within normal range at the screening visit).”
Pela et al. 1999 (47)	“The worsening of the clinical profile of the patient with increased cough, dyspnoea and expectoration with mucopurulent sputum, with or without fever requiring medical intervention.”

Figure 2. Forest plot of pair-wise meta-analysis of the impact of the mucolytic drugs on the odds of COPD exacerbations vs. placebo (A), subset analysis performed on specific mucolytic drugs and doses investigated in high-quality studies (B). Ranking plot for the network of mucolytic agents on the odds of COPD exacerbations (C) in which the treatments have been ranked according to SUCRA (rank of 6 being the worst treatment). Ambr, ambroxol; carbo, carbocysteine; erdo, erdosteine; PCB, placebo; NAC-high, N-acetylcysteine high-dose; NAC-low, N-acetylcysteine low-dose; SUCRA, surface under the cumulative ranking curve. NS, not significant (p ≥ 0.05); ^* p < 0.05.

Table 4. SUCRA values for the impact of mucolytic agents in reducing the odds of COPD exacerbations.

Treatment	SUCRA (%)
Ambroxol	33.2
Carbocysteine	79.0
Erdosteine	70.4
N-acetylcysteine high-dose	68.0
N-acetylcysteine low-dose	26.0
Placebo	24.0

SUCRA: surface under the cumulative ranking curve

Figure 3. Publication bias assessment via funnel plots (left panels) and Egger's test (right panels) for the impact of mucolytic agents (A and B) on the rate of COPD exacerbations vs. placebo, and subset analysis of carbocysteine (C and D) and N-acetylcysteine (E and F). SND, standard normal deviate. ^*p < 0.1.

Figure 4. Meta-regression analysis for study and publication characteristics (A–C), disease characteristics (D–F), ethnicity (G) and corticosteroid therapy (H and I). The lower the log odds ratio the greater the treatment effect on reduction of COPD exacerbations. FEV¹_, forced expiratory volume in 1 second; ICS, inhaled corticosteroids; CS, corticosteroids. ^*p < 0.05: significant interaction between the treatment with mucolytic drugs vs. exacerbation rate and the potential modifier covariates.

Table 5. GRADE evidence profile: mucolytic agents and COPD exacerbations.

		Anticipated absolute effects
Outcome: COPD exacerbation	Quality of the evidence (GRADE)	Risk with placebo	Risk difference with mucolytic agents
Overall (all studies)	⊕⊕⊕ˆ MODERATE^a^b^c	317 per 1000	125 fewer per 1000 (164 fewer to 80 fewer)
N-acetylcysteine, high-dose (high-quality studies with Jaded score ≥ 3)	⊕⊕⊕⊕ HIGH^f	256 per 1000	94 fewer per 1000 (178 fewer to 16 fewer)
N-acetylcysteine, low-dose (high-quality studies with Jaded score ≥ 3)	⊕⊕⊕⊕ HIGH^e	281 per 1000	10 fewer per 1000 (34 fewer to 14 more)
Carbocysteine (high-quality studies with Jaded score ≥ 3)	⊕⊕⊕ˆ MODERATE^b^d	317 per 1000	144 fewer per 1000 (231 fewer to 1 more)
Erdosteine (high-quality study with Jaded score ≥ 3)	⊕ˆˆˆ VERY LOW^g^h	515 per 1000	164 fewer per 1000 (from 59 fewer to 256 fewer)
Ambroxol (high-quality study with Jaded score ≥ 3)	⊕ˆˆˆ VERY LOW^e^g^h	118 per 1000	6 fewer per 1000 (from 41 fewer to 40 more)

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval

GRADE Working Group grades of evidence

High-quality: we are very confident that the true effect lies close to that of the estimate of the effect

Moderate quality: we are moderately confident in the effect estimate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different)

Low-quality: our confidence in the effect estimate is limited (the true effect may be substantially different from the estimate of the effect)

Very low-quality: we have very little confidence in the effect estimate (the true effect is likely to be substantially different from the estimate of effect)

^a. Point estimates vary widely across studies, confidence intervals show minimal overlap, the statistical test for heterogeneity shows a very low P value, and the I² is large

^b. Confirmed by funnel plot and Egger's test

^c. Confirmed by meta-regression

^d. Point estimates vary widely across studies, confidence intervals show no overlap, the statistical test for heterogeneity shows a very low P value, and the I² is large

^e. Confidence interval cross the clinical decision threshold between recommending and not recommending treatment

^f. Point estimates vary across studies, confidence intervals show overlap, the statistical test for heterogeneity shows a low P value, and the I² is large

^g. Only one RCT included in the meta-analysis

^h. Confirmed by OIS analysis

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