Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

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Pulmonary Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/ypupt

Impact of erdosteine on chronic bronchitis and COPD: A meta-analysis T

a,∗ a b a c
Mario Cazzola , Luigino Calzetta , Clive Page , Paola Rogliani , Maria Gabriella Matera
a
Department of Experimental Medicine and Surgery, Chair of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy
b
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK
c
Department of Experimental Medicine, Unit of Pharmacology, University of Campania ‘Luigi Vanvitelli’, Naples, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: A previous meta-analysis suggested that the treatment with erdosteine was associated with significant ameli-
Erdosteine oration of the cumulative global efficacy index and symptoms in comparison to placebo or other mucolytics.
Chronic bronchitis However, this conclusion was criticized because the meta-analysis, as it had been done, made it impossible to
COPD preclude the potential operation of selection biases within and across trials, and identify any realised benefits of
Exacerbation
an individual patient data approach. Taking into consideration these criticisms and also the publication of two
Meta-analysis
further recent articles focused on the prevention of chronic obstructive pulmonary disease (COPD) exacerbations
with erdosteine, we have carried out a quantitative synthesis via meta-analysis of the currently available data on
the use of this drug. Our findings included data from ten studies involving 1278 patients and show that er-
dosteine is able to improve the clinical score of patients with chronic bronchitis and COPD, and also reduces the
overall risk of chronic bronchitis/COPD exacerbations, and reduces the risk of experiencing at least one ex-
acerbation. Furthermore, our data suggest that erdosteine can lengthen the time to the first COPD exacerbation,
reduce the duration of a COPD exacerbation and the risk of hospitalization from COPD. The documented effect of
erdosteine in reducing the occurence and/or influencing COPD exacerbations is important because it indicates
that erdosteine can be added to the list of drugs that can be recommended for treating COPD.

1. Introduction in many Countries since 1995 as a treatment of chronic bronchitis and

COPD [5]. Erdosteine acts by breaking the disulfide bonds of mucus
Mucoactive agents, mucolytics and/or mucoregulators, have two glycoproteins, affecting the physical properties of the mucus, thus
main targets, namely to decrease the mucus hypersecretion and al- leading to increased mucus clearance [5]. It also acts as an antioxidant
terations in the oxidant/antioxidant balance in respiratory diseases through free radical scavenging [6]. Furthermore, erdosteine elicits an
such chronic bronchitis and COPD [1]. anti-inflammatory activity documented by a significant reduction in the
Making mucus easier to expectorate would seem a sensible goal in levels of pro-inflammatory eicosanoids and cytokines in the blood of
the treatment of COPD because it has been shown that mucus hy- COPD patients [7] and in the release of inflammatory mediators due to
persecretion is associated with greater susceptibility to develop COPD, the exercise-induced oxidative stress in severe COPD patients [8]. Im-
an accelerated annual decline in forced expiratory volume in 1 s (FEV1), portantly, erdosteine also has antibacterial effects through reducing
hospitalisations and excess mortality [2]. However, also oxidative stress bacterial adhesiveness [9].
is an important feature of chronic bronchitis and COPD [3] and In 2010, some of us performed a meta-analysis to test the available
therefore targeting oxidative stress or boosting the endogenous levels of evidence that erdosteine treatment in patients with chronic bronchitis/
antioxidants is likely to be beneficial as an additional pharmacological COPD might be effective and accompanied by clinically relevant im-
approach to the treatment of COPD patients [3]. provements [10]. Fifteen trials (1046 patients) were included in the
Many mucolytic agents, such as N-acetyl-L-cysteine, N-acystelyn, analysis. Treatment with erdosteine was associated with a significant
erdosteine, fudosteine, ergothioneine, and carbocysteine lysine salt, amelioration of the cumulative global efficacy index and symptoms in
belong to the cysteine family of drugs are also known to possess po- comparison to placebo or treatment with other mucolytics, but we
tentially important antioxidant properties [4]. concluded that larger long-term studies with fully validated endpoints
Erdosteine [N-(carboxymethylthioacetyl)-homocysteine thio- were required.
lactone] is a drug originally developed as mucolytic agent which is used The Centre for Reviews and Dissemination (CRD), an international

∗
Corresponding author.
E-mail address: [email protected] (M. Cazzola).

https://doi.org/10.1016/j.pupt.2017.11.009
Received 18 October 2017; Accepted 20 November 2017
Available online 09 December 2017
1094-5539/ © 2017 Elsevier Ltd. All rights reserved.
M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

centre engaged exclusively in evidence synthesis in the health field, characteristics, age, gender, smoking habits, FEV1, Jadad score, clinical
determined that this meta-analysis met the Database of Abstracts of score, and exacerbation and hospitalization rates.
Reviews of Effects (DARE) scientific quality criteria for a systematic
review [11]. However, in their comments, they highlighted that the 2.4. Endpoints
article did not present a flow diagram of article inclusion and exclusion.
All of the included studies were supplied by the manufacturers, which The primary endpoint of this quantitative synthesis was the impact
made evaluation of potential bias difficult. They also pointed out that of erdosteine on the clinical score of patients with chronic bronchitis
we did not report how individual patient data were used to standardise and/or COPD, and the rate of exacerbations, compared to control va-
definitions of outcomes and subgroups, generate effects across trials in a lues in placebo/control groups, or at baseline. The secondary endpoint
consistent manner, and verify the validity of the raw data. Individual was the influence of erdosteine on the duration of exacerbation and rate
patient covariates were not included in subgroup analyses and trial of hospitalization.
level covariates were not subject to interaction tests. It was, therefore,
impossible to preclude the potential operation of selection biases within
and across trials, and identify any realised benefits of an individual 2.5. Quality score, risk of bias and evidence profile
patient data approach. Additional uncertainty came from high hetero-
geneity within results and a lack of clear definition of clinical sig- The Jadad score, with a scale of 1–5 (score of 5 being the best
nificance. quality), was used to assess the quality of the randomized clinical trials
In light of these criticisms and the recent publication of two further (RCTs) concerning the likelihood of biases related to randomization,
articles focused on the prevention of acute exacerbations of COPD and double blinding, withdrawals and dropouts [20]. Two reviewers in-
ability to reduce their duration with erdosteine [12,13], we have car- dependently assessed the quality of individual studies, and any differ-
ried out a quantitative synthesis via meta-analysis of the currently ence in opinion about the quality score was resolved by consensus.
available data with this drug in order to provide consistent and The risk of publication bias was assessed by applying the funnel plot
homogeneous findings that may help better clarify the real impact of and Egger's test through the following regression equation: SND = a +
erdosteine in improving the clinical score of patients with chronic b × precision, where SND represents the standard normal deviation
bronchitis and/or COPD, and the use of this drug in preventing chronic (treatment effect divided by its standard error [SE]), and precision re-
bronchitis/COPD exacerbations. presents the reciprocal of the standard error. Evidence of asymmetry
from Egger's test was considered to be significant at P < .1, and the
2. Methods graphical representation of 90% confidence bands are presented as
described elsewhere [20].
2.1. Search strategy The optimal information size (OIS) was calculated as previously
reported [21,22], and the quality of the evidence assessed in agreement
This meta-analysis has been registered in PROSPERO (registration with the Grading of Recommendations Assessment, Development, and
number: CRD42017068372), and performed in agreement with the Evaluation (GRADE) system [23]. The risk of publication bias and
Preferred Reporting Items for Systematic Reviews and Meta-Analyses GRADE analysis were performed on the effect estimates resulting from
(PRISMA) Statement (Fig. 1) [14]. Furthermore, this synthesis satisfied at least 3 high-quality studies (Jadad ≥3).
all the recommended items reported by the PRISMA-P 2015 checklist
[15]. 2.6. Data synthesis and analysis
We undertook a comprehensive literature search for studies evalu-
ating the impact of erdosteine on chronic bronchitis and/or COPD. In Results of this pair-wise meta-analysis are expressed as
particular, the term “erdosteine” was searched for the active treatment, Standardized Mean Difference (SMD), Relative Risk (RR), Natural
and the terms “chronic bronchitis” OR “chronic obstructive pulmonary Logarithmic transformed Proportion (Log Proportion, PLN) and 95%
disease” OR “COPD” were searched for the diseases. The search was confidence interval (95%CI).
performed in PubMed, Scopus, Embase, Google Scholar and the re- The changes in clinical score are reported as SMD since this outcome
pository database clinicaltrials.gov [16] to provide relevant studies was not always standardized among the studies (i.e. cumulative Global
published up to July 31, 2017. No language restriction was applied. Efficacy Index [cGEI], breathlessness–sputum–cough scale [BCS],
Citations of previously published meta-analyses and relevant reviews Subject's Global Assessment of Disease Severity [SGADS], Physician's
were examined to identify further pertinent studies, if any Global Assessment of Disease Severity [PGADS], and non-specific
[5,9,10,17–19]. clinical score [NSCS]). The risk of COPD exacerbation and hospitali-
zation are reported as RR, and normalized as a function of person-
2.2. Study selection season, where one season includes 3 months [24]. The time to first
exacerbation and the duration of exacerbation are reported as PLN.
Studies reporting the effect of erdosteine vs. placebo/control/ Moderate to high levels of heterogeneity were considered for I2 ≥ 50%
baseline in patients with chronic bronchitis and/or COPD have been [16].
selected. All studies assessing the impact of erdosteine on clinical score Since data were selected from a series of studies performed by re-
(s) and the rate of exacerbations of chronic bronchitis and/or COPD searchers operating independently, and a common effect size cannot be
have been included in the analysis. No restriction on the duration of the assumed, the random-effects model was used in order to balance the
treatment was applied. study weights and to adequately estimate the 95%CI of the mean dis-
Two reviewers independently checked the relevant studies identi- tribution of the effect of the active medication on the investigated
fied from the literature searches and databases. Studies were selected in variables [24].
agreement with the previously mentioned criteria, and any difference in Subset analyses were performed by excluding the low-quality stu-
opinion about eligibility was resolved by consensus. dies characterized by Jadad score < 3, and considering specifically
patients affected by chronic bronchitis and/or COPD.
2.3. Data extraction OpenMetaAnalyst [25] software was used for performing the meta-
analysis, GraphPad Prism (CA, US) software to graph the data, and
Data from included studies were extracted and checked for study GRADEpro to evaluate the quality of evidence [23]. The statistical
characteristics and duration, doses of medication, patient significance was assessed for P < .05.

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M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

Fig. 1. PRISMA flow diagram for the identification of studies included in the meta-analysis concerning the impact of erdosteine on clinical condition and exacerbation rate in patients
with chronic bronchitis and/or COPD.

3. Results Treatment with erdosteine significantly (P < .01 to P < .001)

reduced the overall risk of chronic bronchitis/COPD exacerbations and
3.1. Studies characteristics the risk of experiencing at least one exacerbation vs. control (Fig. 3A
and B, respectively), with no differences (P > .05) compared to the
Results obtained from 1278 patients (52.66% in the active treat- subset analysis performed by including in the synthesis exclusively the
ment group, 47.34 in the control group) were selected from 10 pub- studies that enrolled COPD patients (risk of COPD exacerbation: RR
lished studies, including 6 studies on chronic bronchitis [26–31], 3 0.74, 95%CI 0.61–0.89, I2 31%, P = .24; risk of experiencing at least
studies on COPD [12,13,32], and 1 study on patients suffering from one COPD exacerbation: RR 0.78, 95%CI 0.64–0.96, I2 6%, P = .35). In
both chronic bronchitis and COPD [33]. Eight studies had a Jadad score COPD patients receiving erdosteine, the time to the first exacerbation
≥3 [12,13,26–29,31,32], and 2 studies had a Jadad score < 3 [30,33]. was significantly (P < .001) longer than in untreated subjects
The studies have been published between 1988 and 2017, and the (Fig. 3C).
average duration of the studies was 14.02 weeks. Relevant patient de- Erdosteine also elicited a significant (P < .05) protective effect on
mographics, baselines, study characteristics, treatments, definitions of secondary endpoints, namely the duration of COPD exacerbation and
exacerbation and Jadad score are summarized in Table 1. the risk of hospitalization from COPD (Fig. 3D and E).

3.2. Quantitative synthesis 3.3. Bias and quality of evidence

Erdosteine elicited a beneficial impact on all the primary endpoints A significant level of heterogeneity was detected for the overall
of this meta-analysis. Treatment with erdosteine significantly impact of erdosteine on patients suffering from chronic bronchitis and
(P < .001) improved the clinical score of patients affected by COPD COPD, and the presence of publication bias was confirmed by both
and/or chronic bronchitis vs. control (Fig. 2A), with no differences funnel plot and Egger's test (Fig. 4A and B). The subset analysis on
(P > .05) compared to the subset analysis performed by including in COPD did not provide evidence for either heterogeneity, or bias related
the synthesis exclusively high-quality studies (SMD -0.44, 95%CI -0.70 after applying the funnel plot and Egger's test (Fig. 4C and D). Although
to −0.18; I2 80%, P < .001). A further specific analysis (Fig. 2B) in- heterogeneity resulted from the forest plot for chronic bronchitis, the
dicated that erdosteine significantly (P < .01 to P < .001) improved funnel plot and Egger's test did not find any evidence for any publica-
the clinical condition in both COPD patients (SMD: all studies −0.56, tion bias (Fig. 4E and F). Thus, the bias detected that the overall impact
95%CI -0.94 to −0.17, I2 85%, P < .001; high-quality studies −0.28, on clinical scores was related to the concomitant analysis of both
95%CI -0.50 to −0.06, I2 53%, P = .12) and subjects with chronic chronic bronchitis and COPD. The low level of heterogeneity resulting
bronchitis (SMD -0.72, 95%CI -1.17 to −0.28, I2 85%, P < .001; high- from the meta-analysis of the risk of COPD exacerbation and the time to
quality studies −0.58, 95%CI -1.08 to −0.08, I2 86%, P < .001). the first exacerbation was further confirmed by funnel plot and Egger's

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 Table 1
Patient demographics, baseline and study characteristics.

Study, year Trial Number Study Study Analyzed Drug, dose, Disease Definition of Age (years) Male (%) Current Smoking Post- Acute Clinical Jadad
and Identifier characteristics duration patients duration of characteristics exacerbation smokers history bronchodilator exacerbations score score
M. Cazzola et al.

reference (weeks) treatment (%) (pack- FEV1 (% in previous

years) predicted) year

Dal Negro NCT Multicentre, 52 445 Erdosteine Stable COPD (Stage II “A symptomatic 64.8 73.9 28.8 > 10 51.8 ≥2 SGADS, 5
et al., NCT01032304; randomized, 300 mg b.i.d., and III according to worsening beyond PGADS
2017 RESTORE double-blind, total daily dose GOLD 2007) as normal day-to-
[13] placebo- 600 mg, 52 follows: post- day variations
controlled, weeks bronchodilator FEV1/ and requiring a
parallel-group FVC < 70% change in regular
30% ≤ FEV1≤70% medication and/
predicted (and at or health care
least 0.7 L absolute resources
value) utilisation (e.g.
increased use of
bronchodilators,
treatment with
antibiotics and/or
systemic
corticosteroids,
visit to an
emergency
department,
hospitalization)
Moretti and NA Single-centre, 8 40 Erdosteine Acute exacerbation of “Exacerbations … 70.6 82.5 12.5 51.2 47.5 1.3 BCS 3
Fagna- randomized, 300 mg t.i.d., COPD omissis … were

188
ni, controlled, total daily dose assessed if
2015 single-blind 900 mg, 1.4 changes in
[12] weeks therapy with
antibiotics and/or
oral steroids were
required”
Moretti EQUALIFE Multicentre, 32 124 Erdosteine Stable COPD “New episodes of 67.5 79.9 32.9 > 20 59.2 NA NA 3
et al., randomized, 300 mg b.i.d., (FEV1 < 70%) acute disease with
2004 double-blind, total daily dose muco-purulent or
[32] placebo- 600 mg, 32 purulent sputum,
controlled, weeks cough and at least
parallel-group two of the
following
symptoms:
general malaise,
fever > 38 °C,
breathlessness,
difficulty in
expectoration and
leukocytosis.”
De Castro NA Open label, 2 38 Erdosteine COPD (FEV1/FVC at “Increased 62.0 60.0 NA NA 58.0 NA NSCS 1
Pereira non 350 mg b.i.d., least 10% below volume and
et al., comparative total daily dose normal theoretical purulence of
2000 700 mg, 2 value) and chronic sputum, and
[33] weeks bronchitis (cough worsening of
with expectoration dyspnea”#
occurring for at least
three months per
year, for two
(continued on next page)
Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194
 Table 1 (continued)

Study, year Trial Number Study Study Analyzed Drug, dose, Disease Definition of Age (years) Male (%) Current Smoking Post- Acute Clinical Jadad
and Identifier characteristics duration patients duration of characteristics exacerbation smokers history bronchodilator exacerbations score score
reference (weeks) treatment (%) (pack- in previous
M. Cazzola et al.

FEV1 (%
years) predicted) year

consecutive years
with sputum volume
30 ml/24 h)
Aubier NA Multicentre, 3 170 Erdosteine Stable chronic NA 59.0 58.0 NA NA NA NA cGEI 5
et al., randomized, 300 mg b.i.d., obstructive bronchitis
1999 double-blind, total daily dose with hypersecretion
[26] placebo- 600 mg, 3 (FEV1/FVC at least
controlled, weeks 10% below normal
parallel-group theoretical value)
Marchioni ECOBES Multicentre, 1.2 237 Erdosteine Acute exacerbation of NA 66.0 76.0 NA NA NA NA cGEI 5
et al., randomized, 300 mg b.i.d., chronic obstructive
1995 placebo- total daily dose bronchitis (FEV1/FVC
[27] controlled, 600 mg, 1.2 at least 10% below
double-blind weeks normal theoretical
value)
Bisetti NA Double-blind, 1 27 Erdosteine Acute exacerbation of NA 62.0 68.0 NA NA NA NA cGEI 5
et al., randomized, 300 mg b.i.d., chronic bronchitis
1995 placebo- total daily dose
[28] controlled 600 mg, 1
week
Fioretti and NA Double-blind, 26 132 Erdosteine Chronic bronchitis NA 54.8 71.7 NA NA NA NA NA 3
Bander- randomized, 300 mg b.i.d.,
a, 1991 placebo- total daily dose

189
[31] controlled 600 mg, 26
week
Hotzinger NA Double blind, NA 40 Erdosteine Hypersecretory NA 49.0 75.0 NA NA NA NA cGEI 4
et al., randomized, 300 mg t.i.d., infective bronchitis
1991 placebo- total daily dose (acute bronchitis or
[29] controlled 900 mg relapses of chronic
bronchitis)
Ricevuti NA Double blind, 1 24 Erdosteine Acute infective NA 57.0 42.0 100.0 Heavy NA NA cGEI 2
et al., placebo- 300 mg t.i.d., exacerbation of smokers
1988 controlled total daily dose chronic bronchitis (> 20
[30] 900 mg, 1 cigarettes/
week day)

# Translated from Portuguese.

BCS: breathlessness–sputum–cough scale.
b.i.d.: twice daily.
cGEI: cumulative Global Efficacy Index.
COPD: chronic obstructive pulmonary disease.
FEV1: forced expiratory volume in 1 s.
FVC: Forced vital capacity.
NA: not available.
PGADS: Physician's Global Assessment of Disease Severity.
SGADS: Subject's Global Assessment of Disease Severity.
t.i.d.: three times daily.
Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194
M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

Fig. 2. Overall forest plot of the impact of erdosteine vs. control on clinical score of patients with chronic bronchitis and COPD (A), and subset analysis performed on COPD or chronic bronchitis (B). **P < .01 and ***P < .001 vs. control. BCS:
breathlessness–sputum–cough scale; CB: chronic bronchitis; CGEI: cumulative Global Efficacy Index; COPD: chronic obstructive pulmonary disease; NSCS: non-specific clinical score; PGADS: Physician's Global Assessment of Disease Severity;
test (Fig. 4G and J).
A moderate quality of evidence was detected for the overall clinical
impact of erdosteine on patients having COPD, and chronic bronchitis,
whereas high and low quality of evidence resulted from the specific
analyses performed on data obtained from patients with COPD and
chronic bronchitis, respectively. The GRADE approach showed a high
quality of evidence for the protective role of erdosteine against the risk
of COPD exacerbations and on the time of the first exacerbation.
Detailed results of the GRADE analysis and OIS are reported in Table 2.

4. Discussion

Compared to our previous meta-analysis on erdosteine [10], we

have now avoided including unpublished data on the recommendation
of CRD that the use of unpublished data supplied by the manufacturers
makes evaluation of potential bias difficult [11]. However, while using
this more restrictive approach, the current meta-analysis has confirmed
that erdosteine is able to improve clinical score of patients with chronic
bronchitis and/or COPD. Furthermore, and more importantly, the
present meta-analysis has documented that erdosteine is also able to
reduce the overall risk of chronic bronchitis/COPD exacerbations and
the risk of experiencing at least one exacerbation, lengthen the time to
the first COPD exacerbation, reduce the duration of COPD exacerba-
tions, and also the risk of hospitalization from COPD.
The documented effect of erdosteine in preventing and/or influen-
cing COPD exacerbations is important because it indicates that erdos-
teine can be added to the list of drugs that can be recommended for the
treatment of COPD. The 2017 version of the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) strategy [34], based on the
results of two meta-analyses [24,35] stated that in “in COPD patients
not receiving inhaled corticosteroids, regular treatment with mucolytics
such as carbocysteine and N-acetylcysteine (NAC) may reduce exacer-
bations and modestly improve health status”. It also added that cur-
rently available data do not allow the real target population for mu-
colytic/antioxidant agents because of the heterogeneity of COPD
patients enrolled in the studies, doses of treatments, and concomitant
medications [34].
Erdosteine is currently the only mucolytic/antioxidant agent that
has been evaluated in patients with frequent exacerbations, those that
have experienced two or more COPD exacerbations requiring medical
intervention in the previous 12 months. The recent Reducing
Exacerbations and Symptoms by Treatment with ORal Erdosteine in
COPD (RESTORE) study [13], which enrolled 445 frequent exacer-
bators, demonstrated that erdosteine added on to usual maintenance
therapy for COPD based on local physician practice and the available
guidelines on COPD, reduced the exacerbation rate by 19.4% (0.91
versus 1.13 exacerbations/patient−1/year−1 for erdosteine and pla-
cebo, respectively) and decreased the exacerbation duration irrespec-
tive of event severity by 24.6% (9.55 versus 12.63 days for erdosteine
and placebo, respectively). Interestingly, no significant differences were
observed for either the exacerbation rate or duration of exacerbations
SGADS: Subject's Global Assessment of Disease Severity.

between those patients taking inhaled corticosteroids and those patients

not taking inhaled corticosteroids. The impact of erdosteine on duration
of exacerbations is of particular interest because, to date, it the only
mucolytic/antioxidant agent that has been evaluated on this important
endpoint.
In a meta-analysis that we performed before the results of the
RESTORE study were available erdosteine was within the cluster of the
most effective drugs, regardless of the level of evidence [36]. However,
only N-acetylcysteine 1200 mg/day significantly protected against ex-
acerbations vs. placebo (2 studies analyzed: OR 0.56, 95% CI
0.35–0.92; p < .05; high quality of evidence), albeit that this dose was
twice the recommended dose. The results of the current meta-analysis,
which included also the RESTORE study, suggest that erdosteine is
equally effective to N-acetylcysteine in preventing COPD exacerbations,
but using the approved dosage regimen.

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M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

Fig. 3. Forest plot of the protective effect of erdosteine vs. control on the risk of chronic bronchitis/COPD exacerbations (A), the risk of experiencing at least one chronic bronchitis/COPD
exacerbation (B), the time to the first COPD exacerbation (C), the duration of COPD exacerbation (D), and the risk of hospitalization for COPD (E). *P < .05, **P < .01, and
***P < .001 vs. control.

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M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

Fig. 4. Publication bias assessment via funnel plots (left

panels) and Egger's test (right panels) for the impact of
erdosteine vs. control on clinical score resulting from the
concomitant analysis of both COPD and chronic bronchitis
(A and B), and subset analysis performed in patients af-
fected by COPD (C and D) or chronic bronchitis (E and F).
The analysis of publication bias concerning the risk of
COPD exacerbation is reported in G and H, and that re-
garding the time to the first exacerbation is shown in I and
J. COPD: chronic obstructive pulmonary disease; SND:
standard normal deviate. *P < .1.

We are well aware that meta-analysis provides only the effect esti- Whilst waiting for this comparative pragmatic RCT, the evidence
mates that, by definition, reflect an estimate of the possible impact of provided from this meta-analysis supports the use of erdosteine as add-
the intervention on the investigated outcome(s) and, are in any case, on therapy to prevent COPD exacerbations, especially when adminis-
results by indirect comparisons. Therefore, we strongly believe that a tered to patients with frequent exacerbations.
well-powered RCT that will directly compare the efficacy of erdosteine,
and N-acetylcysteine is highly desirable.

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M. Cazzola et al. Pulmonary Pharmacology & Therapeutics 48 (2018) 185–194

Table 2
GRADE evidence profile.

Outcome Quality assessment: erdosteine compared to control in COPD and chronic bronchitis Quality

Risk of bias Inconsistency Indirectness Imprecision Other considerations

Overall clinical impact on both COPD and chronic Not serious Seriousa Not serious Not seriousb Publication bias strongly suspected. ⨁⨁⨁◯
bronchitis All plausible residual confounding would suggest MODERATE
spurious effect.c
Clinical impact on COPD Not serious Not serious Not serious Seriousd All plausible residual confounding would suggest ⨁⨁⨁⨁
spurious effect. HIGH
Clinical impact on chronic bronchitis Not serious Seriouse Not serious Seriousf None ⨁⨁◯◯
LOW
Risk of COPD exacerbations Not serious Not serious Not serious Not seriousg None ⨁⨁⨁⨁
HIGH
Time to the first COPD exacerbation Not serious Not serious Not serious Not serious h
None ⨁⨁⨁⨁
HIGH
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.

Explanations.
a. I2 = 82%, P < .001.
b. Available sample size 7.06% greater that OIS.
c. Confirmed by funnel plot and Egger's test.
d. Available sample size 57.22% smaller that OIS.
e. I2 = 86%, P < .001.
f. Available sample size 65.88% smaller that OIS.
g. Available sample size 122.04% greater that OIS.
h. Available sample size 335.00% greater that OIS.
COPD: cronic obstructive pulmonary disease; OIS: optimal information size.

Conflicts of interest [16] P. Rogliani, L. Calzetta, F. Cavalli, M.G. Matera, M. Cazzola, Pirfenidone, nintedanib
and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: a sys-
tematic review and meta-analysis, Pulm. Pharmacol. Therapeut. 40 (2016) 95–103.
Mario Cazzola, Luigino Calzetta, and Clive Page are consultants to [17] I. Rahman, Antioxidant therapeutic advances in COPD, Ther. Adv. Respir. Dis. 2
Recipharm who manufacture and market erdosteine. (2008) 351–374.
[18] I. Rahman, Pharmacological antioxidant strategies as therapeutic interventions for
COPD, Biochim. Biophys. Acta 1822 (2012) 714–728.
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