CLINICAL THERAPEUTICSVVOL. 22, NO.

2,200O

Effkacy of Oral Long-Term ZV-Acetylcysteine in Chronic

Bronchopulmonary Disease: A Meta-Analysis of Published
Double-Blind, Placebo-Controlled Clinical Trials

Etienne M. Grandjean, MD,l Philippe Berthet, PhD,2

Ralf Ruffmann, MD,3 and Philippe Leuenberger, MD4
‘Phidalsa Institute for Clinical Investigation, Bern, ZBiometrix SA, Gland, 31npharzam
SA/Zambon Group SPA, Cadempino, and 4Division of Pneumology, Department of
Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

ABSTRACT

Objective: This meta-analysis was performed to assess the possible prophylactic bene-
fit of prolonged treatment with oral N-acetylcysteine (NAC) in chronic bronchitis (CB)
based on qualifying clinical trials. Treatment of acute exacerbations with NAC was not
investigated.
Background: Prolonged treatment with oral NAC has been investigated in a number
of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB
in some but not all trials.
Methods: The trials included in this analysis were selected from a MEDLINE@ search of
the period from January 1, 1980, through June 30, 1995; references in the articles retrieved
in the initial search; and consultation with 2 experts. Selection was based on the following
criteria: published, double-blind. placebo-controlled, chronic bronchopulmonary disease, du-
ration of therapy 22 months, and data sufficient to calculate an outcome variable permitting
direct comparison of studies (effect size) for both NAC and placebo groups. The primary end
point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the
other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for
CB, with an additional criterion in some trials. For the meta-analysis, the end points of indi-
vidual trials were transformed into an effect size as a common outcome.
Results: Of 21 trials initially identified, 8 qualified for inclusion. References from the
8 papers and consultation with the experts produced 8 additional publications, 1 of which
qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study),
600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times
per week. The duration of treatment was 3 months (1 study), 25 months (2 studies), or 6
months (7 studies). The results of this meta-analysis showed a statistically significant ef-
fect size for NAC compared with placebo. The overall value of effect size was -1.37 (95%
CI, -1.5 to -1.25). Sensitivity analyses did not significantly alter these results. In a subset

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0 149-29 I X/001$19.00 209


analysisof trials with the number of acute
exacerbations as a clinical end point, a
mean difference of -0.32 clinical event
(95% CI, a.50 to Xl. IX) was found (ie, a
23% decreasein the number of acute ex-
acerbationscomparedwith placebo).
Conclusion: Thesefindings suggestthat
a prolonged course of oral NAC prevents
acute exacerbations of CB, thus possibly
decreasingmorbidity and healthcare costs.
Key words: N-acetylcysteine, chronic
obstructive pulmonary disease, chronic
bronchitis, prevention, meta-analysis.(C&z
Ther. 2000;22:209-221)
INTRODUCTION
The various forms of chronic bronchitis
(CB) are well-defined clinical entities. ’
The key clinical diagnostic criterion is
daily production of sputumfor ~3 months
per year for 22 consecutive years.1.2Pa-
tients with CB have prolonged periods of
cough with excess mucus and occasional
acute exacerbations, particularly in the
winter. Acute exacerbations include in-
creasedcough, change in sputum color or
quantity, or worsening dyspnea.The treat-
ment of CB has been controversial in
many respects,ashas drug therapy to pre-
vent acute exacerbations.
CB, as well as related clinical syn-
dromes associated with chronic airflow
limitation (chronic obstructive pulmonary
disease [COPD], chronic obstructive
bronchitis [COB], and emphysema), are
major public health issuesbecauseof the
associatedmorbidity and mortality.3 Even
a modestreduction in the incidence or du-
ration of typical episodescould decrease
the total socioeconomicburden of this dis-
ease.4Thus, a reduction in the number of
acute exacerbationsof CB is a major goal
of therapy.“.”
210
CLINICAL THERAPEUTICS”
The use of mucoactive drugs for sec-
ondary prevention of acute exacerbations
of CB and COPD has been advocated for
>2 decades,but these drugs’ therapeutic
efficacy remains controversial.h In addi-
tion to its in vitro mucolytic action (ie,
cleaving of disulfide bonds in mucus),7
N-acetylcysteine (NAC) is a potent an-
tioxidant agent that acts as a prodrug for
cysteine and glutathione.* This mecha-
nism of action has been proposed as a
possible basis for its use in bronchopul-
monary disease.9,‘0NAC has prevented
acute exacerbations of CB and provided
symptomatic relief in some but not all
studies. Thus, there is inconsistent evi-
dence of its efficacy in CB.”
The present study was undertaken to
investigate the clinical efficacy of pro-
longed (2 to 6 months) oral administra-
tion of NAC to prevent (not treat) acute
exacerbations of CB. We used classic
methods of meta-analysis,basedon dou-
ble-blind, placebo-controlled clinical tri-
als published in the literature.
MATERIALS AND METHODS
The following definitions were used
throughout the presentstudy’,*: (1) chronic
nonobstructive bronchitis (simple CB),
characterized by chronic production of
bronchial mucus on most days for r3
months per year for r2 consecutive years;
(2) COB, a form of CB with signsof air-
way obstruction; and (3) COPD, pul-
monary diseasecharacterized by dyspnea
and irreversible or partially reversible air-
flow obstruction, often accompanied by
impaired gas exchange (includes emphy-
semaas well as COB). Becausethe clini-
cal trials analyzed were performed from
1976 through 1994, thesedefinitions may
differ slightly from thosecurrently used.3,‘i
E.M. GRANDJEAN ET AL.
Literature Review and Selection
We began with a comprehensive
MEDLINE@ search using the key words
acetylcysteine, N-acetylcysteine, double-
blind method, and placebo-controlled.
The search included English-, French-,
German-, and Italian-language articles
published from January 1, 1980, through
June 30, 1995. Articles on nonrespiratory
indications were discarded. This search
was supplementedby a review of all ref-
erences in the publications identified in
the MEDLINE@ search.An updating elec-
tronic searchwas performed in November
1999 using combined databases (Bio-
MedLink, MEDLINE@, and Current
Drugs). No additional publications ful-
filled the inclusion criteria.
Textbooks and monographs describ-
ing chronic bronchopulmonary disease
or the so-called mucolytic or mucoac-
tive drugs also were reviewed. Finally, 2
clinical experts (1, pulmonary disease;
1, NAC) were asked to produce or quote
any clinical trial (published or unpub-
lished) on NAC and chronic bron-
chopulmonary disease.
Selection criteria for the meta-analysis
were as follows: double-blind, placebo-
controlled trial; patients with chronic
bronchopulmonary disease; duration of
~2 months; data sufficient to calculate an
outcome variable permitting direct com-
parison (effect size) for both NAC and
placebo groups.Patients’written informed
consent was not a criterion for study in-
clusion. Studies were excluded if they
were uncontrolled, if they addressedan
acute clinical condition, or if the duration
of therapy was <2 months. A further ex-
clusion criterion was nonhomogeneity of
patient groups (especially acute bronchi-
tis and CB).
Two personsindependently abstracted
each study by author, title, journal, year
of publication, NAC dose,duration of ad-
ministration, number of subjectsin NAC
and placebo group, major end point for
each study, and incidence of reported ad-
verse events.
Statistical Analysis
Becausethe primary efficacy variables
were not the samein all the studies(either
global assessment or numberof bronchitic
exacerbations),the effect size wasretained
as a nonmetric common outcome measure
across all selected studies.t2 The effect
size is the standardizeddifference between
the average values of the primary efficacy
variables of each treatment group. Stan-
dardized meansthat the given difference
is divided by its SD. The effect size was
computed for each study from the pub-
lished data.
A summary effect size was then calcu-
lated across studies. This correspondsto
the weighted average of the study-specific
effect sizes,in which the weighting factor
for each study is equal to the inverse of
the estimated variance. This statistical
procedure gives more weight to the re-
sults of large, homogeneousstudies.First
introduced in the behavorial sciences,t3
summary effect size is now commonly ap-
plied to various fields of internal medi-
cine, including chronic bronchopul-
monary disease.t4,15 One treatment is
assumedto be statistically superior to the
other if the 95% CI of the overall stan-
dardized difference (or summary effect
size) does not encompass0.
These calculations were carried out ac-
cording to the method described by Pe-
titti,16 under the assumptionthat the dis-
tribution of efficacy variables was not too
211

far from normal and that the group sizes
were approximately the same in the NAC
and placebo groups. Furthermore, to check
the sensitivity of this type of analysis we
performed 2 types of calculations. First, a
test for statistical homogeneity (Q) was
performed by comparing the weighted av-
erage of the squared differences between
summary and study-specific effect sizes to
an appropriate chi-square distribution, with
the same weights used.
Moreover, because of the clinical ho-
mogeneity of selected trials, we repeated
the analysis on those studies with the num-
ber of acute exacerbations as the primary
efficacy variable. Because calculation of
an effect size was not required, the
weighted mean difference was used.16 The
summary mean difference (mA,) of these
studies was obtained by using the fol-
lowing formula:
X,(wl x mAJ 95% a,
mA$ = = 4.32 to a.18
ZW;
where the weighting factor wi = 1 per vari-
ance for each individual study.
Finally, a further subset of studies was
analyzed after discarding studies not pub-
lished in peer-reviewed journals.
RESULTS
Literature Review
From the initial MEDLINEa selection
(21 papers), 8 studieswere found to con-
tain the appropriate key words. Scanning
of these papers’ references and consulta-
tion with the 2 experts produced 8 addi-
tional publications, I of which qualified
for inclusion (Table I). From this first set
of 16 studies, 7 were discarded because
they did not fulfill rl of the criteria for
212
CLINICAL THERAPEUTICS”
inclusion. Reasonsfor exclusion are listed
in Table I. The remaining 9 studies are
listed in Table II.
In every trial but 1,29the inclusion cri-
teria for patients were based at least on
the definition of CB in the Medical Re-
search Council criteria,’ with additional
requisites in some cases. In 2 trials,26,3’
only smokerswere included. In 1 study,2R
an additional inclusion criterion was se-
vere airway obstruction (ie, forced expi-
ratory volume in 1 second [FEV,] ~50%
of predicted value), whereas in 3 other
studies,2”,26.32 severe airway obstruction
(FEV, 540%, SO%, and 50%, respec-
tively) was a reasonfor exclusion.
Meta-Analysis
The individual values for effect size,
weight, and weighted effect size are pre-
sented in Table III. In all studies, the ef-
4.50 fect size was negative for the number of
episodesand positive for clinical score.
However, the positive score was changed
to allow calculations of weighted effect
size (Table III).
When the effect sizes of all the studies
were compared(Table II), that of study 2
favored NAC by a factor of 10. Because
this wasconsidereda strong sourceof bias,
this study wasdiscardedfrom further analy-
sisto exclude a possiblebiasin favor of the
working hypothesis.
Of the remaining 8 trials, 3 were from
the United Kingdom, 2 from Sweden,and
1 each from Denmark, Germany, and
Italy. All were published between 1976
and 1994. The total number of patients
was 1408, and the number of patients per
study varied between 69 (first controlled
study, published in 197617)and 466 (UK
General Practitioner trial, published in
1987’O).
E.M. GRANDJEAN ET AL.

Table 1. Double-blind, placebo-controlled trials of oral N-acetylcysteine in chronic bron-

chitis: Initial selection from literature sources.

No. of Treatment Selected/ Reason for

Reference Patients Duration Excluded Exclusion

Grassi and Morandini” 69 6mo Selected

Lemy-Deboiset all8 29 15d Excluded Shortduration,no
superinfection,mixed
with acutedisease
Verstraeteni9 60 10d Excluded Shortduration
Aylward et alzO 34 4wk Excluded Shortduration
Brocardet a12’ 95 10d Excluded Shortduration,mixed
with acutedisease
Gepts22 49 7-15 d Excluded Shortduration
Grassiz3 611 6mo Selected
MaesenandBrombache?4 20 6mo Excluded No statisticaldata
available
Ravezet a125 40 14d Excluded Shortduration
Bomanet al26 203 6mo Selected
Jacksonet al*’ 121 3 mo Selected
McGavin28 148 5 mo Selected
Meister29 181 6mo Selected
ParrandHuitson30 466 6mo Selected
Rasmussen andGlennow3’ 91 6 mo Selected
Hansenet al32 129 22 wk Selected

Of the 8 studiesfinally assessed,the over- The meta-analytic method was applied

all effect size was-1.37, with a 95% CI of
between -1.5 and -1.25, which indicated
that NAC was efficacious compared with
placebo(Figure 1). In this set of trials, the
test for homogeneity failed, with Q = 165
(P < 0.001, degreesof freedom [dfl = 7).
Becausethe initial samplewas nonhomo-
geneous,a mathematicalsensitivity analy-
sis was performed, resulting in successive
attempts to obtain a more homogeneous
sampleof trials. Studies (with no specific
clinical features) 1, 4, 6, and 9 (total N =
500) were selected, becausethe zero hy-
pothesisof homogeneitycannot be rejected
(Q = 2.07 for df = 3; 0.5 < P < 0.7).
to this group of trials as describedprevi-
ously, resulting in an effect size of -1.84
(Figure l), with a 95% CI of -2.05 to -1.63.
Limiting the meta-analysisto trials in which
the main commonend point was the num-
ber of acute exacerbationsalso resulted in
statistical homogeneity (Table IV). In this
case,the resultsare expressedasnumberof
clinical events, since use of effect size is
not required. The summary mean differ-
ence for studies 1, 3, 5, 6, 8, and 9 (n =
821) was-0.32, with a 95% CI of -0.50 to
-0.18 (Figure 2). With this set of trials, the
hypothesis of nonhomogeneitycan be re-
jected (Q = 0.02 for df = 5; P > 0.05).

213
Table II. Double-blind, placebo-controlled trials of oral N-acetylcysteine in chronic bronchitis: Secondary selection of literature
sources and major study features.

Study No. of Dosage Primary Effect

No. Reference Patients bg) End Point Size

Grassiand Morandinit7 69 300 BID 3 d/wk No. of episodesin 6 mo -2.056

Grassi*’ 611 200 BID No. of episodes in 6 mo -11.270*
Boman et alz6 203 200 BID No. of episodes -2.498
Jacksonet a127 121 200 TID Clinical assessment -1.966
McGavinz8 148 200 TID No. of exacerbations -2.500
Meister29 181 300 BID slow release No. of episodes -1.659
Parr and Huitson30 466 200 TID Monthly no. of episodes -0.607
Rasmussenand Glennow3t 91 300 BID controlled release No. of episodes -0.314
Hansenet a132 129 600 BID controlled release No. of episodes -1.899

*After this first transformation, study 2 was discarded from further analysis to avoid a possible bias in favor of the test treatment because of a striking discrepancy
compared with the other 8 studies.
E.M. GRANDJEAN ET AL.

Table III. Details of effect size values for clinical trials of oral N-acetylcysteine in chron-
ic bronchitis.

Study Primary No. of Effect Weighting Weighted

No. Reference End Point Patients Size Factor Effect Size

Grassi and Morandinir7 No. of episodes 69 -2.056 11.28 -23.20

Boman et a126 No. of episodes 203 -2.498 28.51 -71.22
Jackson et al*’ Clinical assessment 121 (-)1.966* 20.40 40.10
McGavinz8 No. of episodes 148 -2.500 20.77 -51.93
Meister29 No. of episodes 181 -1.659 33.67 -55.85
Parr and Huitson’O Monthly rate of 466 -0.607 95.60 -58.03
episodes
8 Rasmussen and Glennow3’ No. of episodes 91 -0.314 22.47 -7.06
9 Hansen et a13* No. of episodes 129 -1.899 22.23 -42.21
Total 1408 254.93 -349.60

*In the 1 study in which the primary end point was clinical assessment, any clinical improvement resulted in a
positive number (higher score). In the other studies, with the number or frequency of acute exacerbations as
the major end point, improvement resulted in a negative number (decrease). For the homogeneity of further
analysis. all values are given as negative numbers, with a (-) for study 4.

Favors placebo
1

0
Favors NAC
0

-1 -

+
0

0 0 +
-*- 0

0 0

-3 -
I I 1 I I I I I I I I I
1 2 3 4 5 6 7 8 9 # all
Study No.

Figure 1. Effect sizes (measured in SD) of the 8 studies in the meta-analysis. Each point rep-
resents the effect size for the individual study; 95% CIs (ie, 1.96 in SD units) are
not shown. All = summary effect size of 8 pooled studies (study 2 was discarded
because of an outlying value); # = resulting value when studies 1,4,6, and 9 were
selected empirically after homogeneity testing and pooled; vertical lines = 95%
CIs of the summary effect sizes of all and #; NAC = N-acetylcysteine.

215
 CLINICALTHERAPEUTICS"

Table IV. Clinical trials of oral N-acetylcysteine in chronic bronchitis having the number
of acute exacerbations as a major end point: Mean differences.

Study Primary No. of Mean

No. Reference End Point Patients Difference Variance

1 Grassi and Morandini” No. of episodes 69 -0.683 0.080

3 Boman et alz6 No. of episodes 203 -0.490 0.038
5 McGavinZs No. of episodes 148 4.500 0.080
6 Meister?” No. of episodes 181 -0.276 0.027
8 Rasmussen and Glennow” No. of episodes 91 -0.080 0.064
9 Hansen et al”* No. of episodes 129 -0.289 0.023

0.4

Favors placebo

I
Favors NAC

-0.4 -

-0.8 -

I I I I I I I

1 3 5 6 8 9 Summary Mean
Study No.

Figure 2. Mean difference in the number of acute exacerbations in each trial having this
as the primary end point and in the pool of 6 studies (summary mean). Each
point indicates the mean difference; vertical lines are the 95% CIs.

This value of -0.32 corresponds to the
difference between the number of clinical
events recorded in the placebo and NAC
groups during follow-up. If the number of
acute exacerbations in the placebo group
is considered as 100% of expected events,
then a reduction of 23% (95% CI, -12%
to -33%) in the end point events is ob-
tained in the treatment group (Figure 3).
Further selecting only trials published
in peer-reviewed journals (studies 1, 3, 5,
8, and 9; n = 640) did not modify the out-
come of the analysis. The summary mean
difference was Xl.36 (95% CI, -0.55 to

216
E.M. GRANDJEAN ET AL.

1.6 -
1.4 -
z 1.2-
s
32 l-
dcD
= .g 0.8 -
sg
r” “0 0.6 -
8 0.4 -
0.2 -
0 I I
Placebo N-acetylcysteine

Figure 3. Overall effect of treatment with oral N-acetylcysteine on the incidence of

episodesof acute exacerbationsof chronic bronchitis during the period of ob-
servation. *95% CI, -33% to -12%.

-0.18). Here, too, statistical homogeneity The various measurestaken to detect a

was obtained (Q = 0.025; P > 0.05).
Adverse Effects
Oral treatment with NAC was well tol-
erated. Adverse effects were usually mild,
mostly gastrointestinal, and did not re-
quire treatment interruption. There were
no significant differences between groups.
DISCUSSION
CB is characterized by recurrent acute ex-
acerbations that increase morbidity and
health care costs. Furthermore, the dis-
easemay lead to progressive impairment
of pulmonary function and eventually to
chronic airway limitation. Therefore, pre-
venting acute exacerbations is a major
therapeutic goal.
The present meta-analysis showed a
definite, statistically significant effect of
long-term oral NAC treatment on mor-
bidity from CB compared with.placebo.
possible bias due to the use of different
end points or to correct for nonhomoge-
neous trial populations did not alter the
overall result of the meta-analysis.
As with any meta-analysis, however,
some caution is required to interpret the
results.33,34It is widely acceptedthat pos-
itive results from clinical trials tend to be
published more frequently than do nega-
tive or inconclusive findings,35 resulting
in a possiblebias in a meta-analysis de-
voted exclusively to published trials. This
is improbablein the presentmeta-analysis,
since ~3 of the 8 published trials included
(studies 5, 7, and 8; Table III) are what
are usually considered “negative” trials;
in none of these trials did reduction of
acute exacerbations attain statistical sig-
nificance. In addition, 1 published trial
(study 2) which had an effect size that
was disproportionally high comparedwith
the other studies and could therefore be
seenasoveroptimistic, wasdiscardedfrom
the analysis.

217

Another cause for caution is the dis-
parity between dosesin the various trials,
which ranged from 600 mg 3 times per
week to 600 mgld, with 400 mgld usedin
several studies. However, 400 mg/d is
now consideredthe lower limit of the rec-
ommendeddose,s6and 1200or even 1800
mg/d, recognized as safe for other indi-
cations,s7-“” is increasingly being advo-
cated for bronchopulmonary disease as
well. It should be noted that even a rather
low dose, as was usual when these trials
were performed, produceda positive over-
all result.
Of greater relevance is the issueof se-
lection criteria, especially the severity of
CB and, in particular, of airway obstruc-
tion associatedwith CB. The results tend-
ed to be poorer in trials in which patients
had a higher degreeof airway obstruction
compared with those in which patients
had mild obstructive disease.Such differ-
ences in selection criteria may contribute
to the nonhomogeneity of the clinical tri-
als used in the present study.
Hence, the results of the present meta-
analysis suggest that 3 to 6 months of
therapy with NAC resultsin a definite, al-
though not extreme, reduction in the ex-
pected number of acute exacerbations of
CB and may thus decreasemorbidity and
health care costs. This conclusion appears
to contrast somewhat with the view that
mucoactive drugs have a limited or in-
significant effect on mucus modification
in vivo. The present results suggestthat
the mechanism of action responsible for
NAC’s clinical effect may differ from
mere mucoactive properties. In fact, this
possibility was considered>lO years ago,
when Richardson wrote: “Here is a para-
dox: the drug probably does bring some
benefit to chronic bronchitic patients, but
not in the way it was designed to.“40 In
218
CLINICAL THERAPEUTICS”
addition to its recognized antioxidant prop-
erties8 NAC may also have a direct bac-
teriostatic effect on intrabronchial micro-
bial flora.41
CONCLUSIONS
The presentmeta-analysispointsto a favor-
able, statistically significant effect of pro-
longed (23 months)oral NAC treatmenton
the courseof CB. This effect was particu-
larly evident in the prevention of acute ex-
acerbationsof CB, which was the primary
end point in the majority of trials reviewed.
ACKNOWLEDGMENTS
This work was supported by a grant from
Inpharzam SA/Zambon Group SpA, Cad-
empino, Switzerland.
The authors thank 0. Dalesio, MD,
PhD, for review of the data and K. Kremer
for reviewing and editing the manuscript.
Address correspondence to: Philippe
Leuenberger,MD, Division de pneumolo-
gie, Departement de medecine interne,
CHUV, Rue du Bugnon 17, CH- 1011 Lau-
sanne,Switzerland.
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