High-Dose N-Acetylcysteine in Stable COPD
The 1-Year, Double-Blind, Randomized,
Placebo-Controlled HIACE Study
Hoi Nam Tse , MBChB, FCCP ; Luca Raiteri , MD ; King Ying Wong , MBBS ;
Kwok Sang Yee , MBBS ; Lai Yun Ng , MBChB ; Ka Yan Wai , MBBS ;
Ching Kong Loo , MBBS ; and Ming Houng Chan, MBBS
CHEST July 2013; 144(1):106–118
Journal Club Presentation
Dr Muhammed Aslam
Department Of Pulmonary Medicine
• The mucolytic and antioxidant effects of N-
acetylcysteine (NAC) may have great value in
• However, beneficial effects have not been
confirmed in clinical studies, possibly due to
insufficient NAC doses and/or inadequate
outcome parameters used.
• The objective of this study was to investigate
high-dose NAC plus usual therapy in Chinese
patients with stable COPD.
• The imbalance of oxidant/antioxidant agents
(redox balance) plays an important role in
• Inhaled cigarette smoke, the main exogenous
source of oxidative stress in COPD, stimulates
elastase activity and induces apoptosis,
resulting in lung damage and emphysema .
• Oral N-acetylcysteine (NAC) is a mucolytic agent
with direct/indirect antioxidant and antiinflammatory
properties that may be beneficial in COPD.
• NAC acts directly as a reactive oxygen species
scavenger and acts as a precursor of reduced
• NAC restores cellular redox status and modulates the
inflammatory pathway in COPD by inhibiting redox
sensitive cell-signal transduction and pro inflammatory
Study Design and Methods
• This 1-year, double-blind, randomized, placebo-
controlled trial was conducted in Kwong Wah Hospital,
• Patients were recruited from the COPD clinic from
March 1,2010, to February 28, 2011.
• Subjects aged 50 to 80 years, with stable COPD and
post bronchodilator spirometry FEV 1 /FVC ratio , 0.7
were included in the study.
• Eligible patients experiencing an acute exacerbation
were treated appropriately and they were recruited 4
weeks after remission of their exacerbation.
• Coexisting pulmonary diseases, such as
interstitial lung or active infectious diseases
• Refused to participate or failed to cooperate
• If dyspnea severity prevented lung function
• Patients on long-term bilevel pressure
ventilation or long term oxygen therapy with
chronic respiratory failure
• All eligible patients with COPD gave their
written informed consent and underwent a 4-
week run-in period before randomization.
• Usual mucolytic treatments, if any, were
stopped in the 4-week run-in period.
Randomization and Blinding
• After the 4-week run-in period, eligible patients with
COPD were randomly allocated to NAC 600 mg bid or
• For blinding, NAC and placebo were identical in
appearance (a 600-mg effervescent tablet ).
• Patients and investigators were blinded to treatment
allocation during the study.
• Randomization and allocation details were known only
to a third party.
• Recruited subjects were managed by their physicians in
the usual manner, with NAC or placebo prescribed in
addition to usual drug treatment according to GOLD
• Monitored patient progress every 16 weeks
• Primary outcome measurements were small
airways function parameters: FEF 25%-75%
and FOT (Forced Oscillation Technique)
• Inspiratory capacity (IC), FEV 1 , and FVC were
Secondary outcome measurements
• COPD exacerbation rate (as defined by two of the
following three symptoms: increase in shortness
of breath, volume, or purulence of sputum)
• Hospitalization rate due to COPD exacerbations
• Dyspnea (modified Medical Research Council
[mMRC] dyspnea scale)
• Qualityof life (St. George’s Respiratory
Other baseline, information collected -
• Demographic characteristics(age, sex)
• Current medications & medical co morbidities.
• mMRC dypsnea score
• lung function tests
• SGRQ score
• 6-min walking distance (6MWD)
• Symptoms were recorded at each follow-up visit
• The physician checked compliance to treatment by
counting the number of returned tablets.
• Good compliance to treatment was defined as the
consumption of 70% of dispensed medication.
• Adverse drug effects, exacerbation episodes, and
recent changes in current medications were recorded
at follow-up visits.
• Lung function tests, such as spirometry, FOT, SGRQ
score, and 6MWD, were measured at 0, 16, and 52
• Of 133 eligible patients 108 patients completed the study -
Baseline Characteristics of the Study Subjects
• No significant differences between treatment and placebo
groups at baseline.
• The frequencies of COPD exacerbation and admissions in
the previous year were also similar in the two groups.
• The majority of the subjects were elderly, male exsmokers
with moderate to severe COPD
• Similar proportions of subjects were receiving inhaled
corticosteroids, long-acting muscarinic agonists, and
combined inhaled corticosteroids and long-acting beta
agonists in both groups.
• There were no significant differences in FEF 25%-
75% between study groups at baseline.
• During 1-year follow-up, there was a significant
improvement in FEF 25%-75% with NAC (from
0.72 +/- 0.07 L/s to 0.80 +/-0.07 L/s)
• FEF 25%-75% remained static with placebo (from
0.679 +/- 0.07 L/s to 0.677 +/- 0.07 L/s)
• There were no significant differences for changes
in other spirometric parameters (FEV 1 , FVC, and
IC) between NAC and placebo during the study
• FOT— Over 1 year, reactance improved
significantly with NAC vs placebo
• Reactance at 6 Hz improved with NAC,
whereas it deteriorated with placebo ( 1 0.48 [
1 22.3%] vs 2 0.22 [ 2 10.7%]
• FRes was significantly reduced with NAC vs
placebo ( 2 5.86 [ 2 21.7%] vs 2 1.03 [ 2 3.7%]
• NAC also provided significant improvement in
• FDep improved (decrease in negativity) with
NAC and deteriorated (increase in negativity)
Frequency of COPD Exacerbations:
• Of 146 COPD exacerbations recorded during
the study, 50 occurred with NAC and 96
occurred with placebo.
• The mean frequency of COPD exacerbations
with NAC was significantly lower than placebo
Frequency of Admissions Due to COPD
• NAC had a lower mean COPD admission
frequency (NAC 0.5/y vs placebo 0.80/y
• Lower hospitalization days due to COPD
exacerbation (NAC 1.8 d/y vs placebo 4.2 d/y)
• There were no differences between NAC and
placebo in terms of respiratory symptoms
(mMRC dypsnea score), quality of life (SGRQ),
and exercise capacity (6MWD)
• Adverse Effects
No major adverse effects occurred in either
• High-dose NAC (600 mg bid) was a well
• It significantly decreased small airways
resistance, as shown by improvements in FEF
25%-75% and FOT, and reduced exacerbation
frequency in patients with stable COPD.
• Compared with placebo, study showed that
high dose NAC treatment provided significant
improvements in FEF 25%-75% and in
reactance (reactance at 6 Hz and FRes) and
resistance (resistance at 6 Hz and FDep).
• This is the first study that has evaluated and
demonstrated the efficacy of high-dose NAC
treatment on small airways function in
patients with COPD.
• Despite most previous studies failing to show
a beneficial effect with NAC 600 mg daily in
COPD this study demonstrated that 1-year,
high-dose, NAC (600 mg bid) improved small
airways function in patients with COPD.
• The difference between this study and
previous research may be attributed to the
higher dosage of NAC used, as it has been
suggested that NAC’s antioxidant effect is
• In vitro studies revealed that NAC exerts its
mucolytic effect at low doses, whereas the
antioxidant effect appears only at higher
doses (1,200-1,800 mg daily).
• This study failed to show a significant effect of high-dose
NAC on COPD symptoms, exercise capacity, or quality of life
• Possible reasons for this are
1)the small sample size might have had inadequate power
to achieve statistical significance for these clinical
2)Unlike bronchodilators, NAC acts on COPD through its
antioxidant, antiinfl ammatory, and mucolytic properties.
Therefore, NAC might not relieve dyspnea directly in
patients with COPD, although a beneficial effect in small
airways function was demonstrated
• The sample size in this study was too small to
detect improvement in lung function
parameters (ie, FOT) with NAC and the study
may be underpowered to detect changes in
other clinical parameters.
• Therefore, studies with larger sample sizes are
warranted to assess the effects of
maintenance treatment with high-dose NAC in