To investigate the effect of oral N-acetylcysteine (NAC) in treating chronic bronchitis.

The authors searched MEDLINE from 1966 to July 1999, EMBASE from 1982 to July 1999, and the Cochrane Library (Issue 2, 1999) using the free text terms: 'N-acetylcysteine', 'NAC', 'fluimucil' and 'bronchitis', and combinations of these terms. Additional relevant studies were identified by searching the bibliographies of retrieved studies and systematic reviews, and by contacting three manufacturers for in-house databases on NAC and relevant unpublished data. No language restrictions were reported.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were included.

Specific interventions included in the review

NAC given orally, two or three times daily, at doses of 400 or 600 mg/day compared with placebo. Treatment periods ranged from 4 to 32 weeks.

Participants included in the review

Adult patients with chronic bronchitis. The percentages of patients per trial who were smokers or ex-smokers ranged from 72 to 100%. Patient characteristics, risk factors and lung function varied across the studies and were reported inconsistently.

Outcomes assessed in the review

Prevention of exacerbations, defined according to clinical symptoms; improvement in symptoms; and gastrointestinal adverse effects. Data on forced expiratory volume in one second (FEV1), peak flow, and viscosity and volume of mucus were not analysed because these were considered to be surrogate end points, and were also reported inconsistently.

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.

The studies were assessed using the 5-point Jadad score on randomisation, blinding and description of withdrawals (see Other Publications of Related Interest). Each of the five authors independently assessed the quality of each study. Authors met to achieve consensus.

The authors do not state how the data were extracted for the review, or how many of the reviewers performed the data extraction.

Data were extracted for the categories of: study identification, information about patients, dose of NAC treatments, study period, concomitant medication, study end points, and drug-related adverse effects.

Dichotomous data on prevention of exacerbation, improvement of symptoms, and adverse effects were extracted from the original studies.

The relative benefit or relative risk (RR), number-needed-to-treat (NNT) and number-needed-to-harm (NNH) were calculated for individual trials, along with 95% confidence intervals (CIs).

How were the studies combined?

The relative benefit or RR, along with 95% CIs, were calculated for combined trials using a fixed-effect model. The NNT or NNH and their 95% CIs were also calculated for combined trials.

How were differences between studies investigated?

The authors do not report a method for assessing heterogeneity.

A sensitivity analysis was performed to assess the impact of trial size on the results.

Eleven RCTs were included in the review with 2,540 participants randomised to either NAC or placebo. Only 2,011 participants were included in the statistical analysis (996 received NAC and 1.015 received placebo).

Study quality: drop-out rates were highest (35.5%) in the largest trial. The mean validity score was 4 points (range: 3 - 5). All but three trials used placebo and NAC tablets of identical shape, form and taste.

In 9 trials, 351 of 723 participants (48.5%) receiving NAC had no exacerbation, compared with 229 of 733 participants (31.2%) receiving placebo. The relative benefit was 1.56 (95% CI: 1.37, 1.77) and the NNT 5.8 (95% CI: 4.5, 8.1).

In 5 trials, 286 of 466 participants (61.4%) receiving NAC reported improvement of their symptoms, compared with 160 of 462 participants (34.6%) receiving placebo. The relative benefit was 1.78 (95% CI: 1.54, 2.05) and the NNT 3.7 (95% CI: 3.0, 4.9).

In 6 trials with NAC, 68 of 665 participants (10.2%) reported gastrointestinal adverse effects, compared with 73 of 671 participants (10.9%) taking placebo. The RR was 0.96 (95% CI: 0.70, 1.30). The NNH (-153, 95% CI:-25, +38) is reported, but appears to be in error since the reported NNH lies outside the confidence range.

In 10 trials with NAC, 79 of 1,207 participants (6.5%) withdrew from the study due to adverse effects, compared with 87 of 1,234 participants (7.1%) taking placebo. The RR was 0.92 (95% CI: 0.69, 1.23). The NNH (-198, 95% CI:-40, +67) is reported, but appears to be in error since the reported NNH lies outside the confidence range.

In the sensitivity analysis, there was no evidence of any relationship between group size and control event rate, relative benefit or NNT.

The authors state that the treatment of patients with chronic bronchitis with oral NAC for approximately 3 to 6 months is associated with a statistically-significant decrease in the risk of exacerbations, and an even greater effect on bronchitic symptoms compared with placebo, without increasing the risk of adverse effects. Whether this benefit is sufficient to justify the routine and long-term use of NAC in all patients with chronic bronchitis should be addressed in further studies.

The authors stated the research question and inclusion and exclusion criteria. The literature search was reasonably thorough and was not restricted to English language publications. There were no tests for publication bias.

The quality of the included studies was formally assessed and the authors have reported the quality scores of the included studies. The authors have not reported how the articles were selected, or who performed the selection and data extraction.

The data extraction is reported in tables and discussed in the text of the review. The studies were statistically combined, although no tests for heterogeneity were performed. A sensitivity analysis was performed to investigate the influence of size of included trials on the results, and there is some discussion of possible biases in the text of the review.

The authors' conclusions appear to follow from the results but should be viewed with caution because of limitations in the quality of the review process.

Practice: The authors did not state any implications for further practice.

Research: The authors state that future trials should include intention to treat analyses and cost-effectiveness studies to assess whether routine and long-term use of NAC would benefit all patients with chronic bronchitis, or whether there are specific subgroups that would benefit most. There is also a need for studies to examine beneficial and adverse effects of regular treatment over longer periods of time.

Swiss National Research Foundation, PROSPER grant number 3233- 051939.97.

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.