Twice Daily N-Acetylcysteine 600 Mg for Exacerbations of Chronic Obstructive Pulmonary Disease (Pantheon): A Randomised, Double-Blind Placebo-Controlled Trial

Abstract

SummaryBackground. Increased oxidative stress and inflammation has a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Drugs with antioxidant and anti-inflammatory properties, such as N-acetylcysteine, might provide a useful therapeutic approach for COPD. We aimed to assess whether N-acetylcysteine could reduce the rate of exacerbations in patients with COPD. Methods. In our prospective, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 40-80 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV1) / forcedvital capacity < 0.7 and FEV1 of 30-70 % of predicted) at 34 hospitals in China. We stratified patients according to use of inhaled corticosteroids (regular use or not) at baseline and randomly allocated them to receive N-acetylcysteine (one 600 mg tablet, twice daily) or matched placebo for 1 year. The primary endpoint was the annual exacerbation rate in patients who received at least one dose of study drug and had at least one assessment visit after randomisation. This study is registered with the Chinese Clinical Trials Registry, ChiCTR-TRC-09000460. Findings. Between June 25, 2009, and Dec 29, 2010, we screened 1 297 patients, of whom 1 006 were eligible for randomisation (504 to N-acetylcysteine and 502 to placebo). After 1 year, we noted 497 acute exacerbations in 482 patients in the N-acetylcysteine group who received at least one dose and had at least one assessment visit (1.16 exacerbations per patient-year) and 641 acute exacerbations in 482 patients in the placebo group (1.49 exacerbations per patient-year; risk ratio 0.78, 95% CI 0.67-0.90; p = 0.0011). N-acetylcysteine was well tolerated: 146 (29 %) of 495 patients who received at least one dose of N-acetylcysteine had adverse events (48 serious), as did 130 (26 %) of 495 patients who received at least one dose of placebo (46 serious). The most common serious adverse event was acute exacerbation of COPD, occurring in 32 (6 %) of 495 patients in the N-acetylcysteine group and 36 (7 %) of 495 patients in the placebo group. Interpretation. Our findings show that in Chinese patients with moderate-to-severe COPD, long-term use of N-acetylcysteine 600 mg twice daily can prevent exacerbations, especially in disease of moderate severity. Future studies are needed to explore efficacy in patients with mild COPD (GOLD I). Key words: chronic obstructive pulmonary disease, acute exacerbation, antioxidant therapy, N-acetylcysteine, high dose. РезюмеУсиление воспалительных и окислительных процессов играет важную роль в патогенезе хронической обструктивной болезни легких (ХОБЛ). При этом заболевании может быть эффективно применение лекарств с противовоспалительной и антиоксидантной актив-

Acute exacerbation of COPD

“…The oral phosphodiesterase‐4 inhibitor, roflumilast, is associated with fewer exacerbations in COPD patients with a phenotype of chronic bronchitis and history of prior exacerbations . Oral mucolytic agents such as N ‐acetylcysteine also reduce acute exacerbations . Vaccination against both influenza and pneumococcal infections is advocated as part of overall care of COPD patients.…”

Increased CD8 T‐cell granzyme B in COPD is suppressed by treatment with low‐dose azithromycin

“…To further dissect the effect of azithromycin on CD4 and CD8 T cells, we therefore investigated granzyme B production in T cells exposed to azithromycin (at concentrations that are physiologically relevant) in an in vitro model of T‐cell activation. Given the suggested role of high‐dose n‐acetyl cysteine in reducing COPD exacerbations, we assessed this treatment in parallel with azithromycin. Granzyme B was produced by less than 5% of non‐stimulated T cells.…”

“…To evaluate the effects of azithromycin and n‐acetyl cysteine on granzyme B production, an in vitro assay was utilized . N‐acetyl cysteine was investigated based on its reported effectiveness in preventing exacerbations in COPD . Mononuclear cells were isolated from peripheral blood from the five healthy human donors using Lymphoprep (Axis‐Shield, Oslo, Norway), according to manufacturer's instructions.…”

Pharmacotherapy in Copd- Recent Innovations and Research

“…19 Contrary to these findings, a study from china gives a new hope as N-acetylcysteine in double dose reduced the number of exacerbations when given along with backup inhaled treatment, but head-to-head comparison is still needed. 20 There were some concerns regarding the drug delivery in COPD especially with tiotropium given by Respimat device. Studies showed more number of deaths in the treatment arm as compared to placebo.…”