High-Dose N-Acetylcysteine in Stable COPDThe 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

Junior Resident Department Of Pulmonary Medicine ACME Pariyaram

Background:

• The mucolytic and antioxidant effects of N-acetylcysteine (NAC) may have great value in COPD treatment.

• 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 COPD pathogenesis.

• 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 glutathione (GSH).

• NAC restores cellular redox status and modulates the inflammatory pathway in COPD by inhibiting redox sensitive cell-signal transduction and pro inflammatory gene expression.

Study Design and Methods

• This 1-year, double-blind, randomized, placebo-controlled trial was conducted in Kwong Wah Hospital, Hong Kong

• 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.

Exclusion criteria

• Coexisting pulmonary diseases, such as interstitial lung or active infectious diseases (eg, TB),

• Refused to participate or failed to cooperate• If dyspnea severity prevented lung function

testing.• 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 placebo

• 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

Outcome Measures

• Monitored patient progress every 16 weeks• Primary outcome measurements were small

airways function parameters: FEF 25%-75% and FOT (Forced Oscillation Technique) parameters

• Inspiratory capacity (IC), FEV 1 , and FVC were also measured

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

Questionnaire [SGRQ])

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 (every16 weeks).

• 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 weeks.

Results• Of 133 eligible patients 108 patients completed the study - NAC=52;

placebo=56Baseline 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 period

• 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 resistance

• FDep improved (decrease in negativity) with NAC and deteriorated (increase in negativity) with placebo

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 Exacerbation

• 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

group.

Conclusion

• High-dose NAC (600 mg bid) was a well tolerated treatment.

• 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.

Discussion

• 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 dose dependent.

• 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 parameters.

• Possible reasons for this are 1)the small sample size might have had inadequate power to

achieve statistical significance for these clinical parameters.

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 COPD.

Thank You !!!!!