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N-acetylcysteine in chronic bronchitis

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Outcomes
Results
Efficacy
Harm
Comment
One of the interesting differences between nations (and especially European nations) is that treatments considered efficacious in one are considered useless in another. One example is N-acetylcysteine for chronic bronchitis. This is widely prescribed in some parts of Europe, but not in the anglophone world. A systematic review tells us that it had benefit without harm [1].

Search

The strategy was wide, using three electronic databases, including the Cochrane Library, previous reviews [2] and contacting manufacturers. It was not restricted by language. Randomised comparisons between N-acetylcysteine and placebo were sought in order to answer the question of whether N-acetylcysteine had any efficacy.

Outcomes

Two efficacy outcomes were sought. First was the prevention of any exacerbation of chronic bronchitis. This would generally be regarded as increase in cough, sputum volume or purulence, or dyspnoea. The second efficacy outcome was patients reporting unequivocal improvement of their bronchitis symptoms. This included patients rating their treatment as good or excellent.

Information on adverse effects was also used, either as specific adverse effects, or as withdrawal from a trial because of adverse effects.

Results

There were eleven randomised trials with 2,500 patients randomised, and information on 2,000 patients for analysis. N-acetylcysteine doses were 400-600 mg a day in two or three oral doses. Because studies were generally of long duration (mostly 12 weeks or longer) there were dropouts, and because many of the trials were old, an intention to treat analysis was not possible. Eight trials used identical N-acetylcysteine and placebo tablets. Trials were of high quality, all scoring three or more on a scale up to five points; three scored three, seven scored four and one scored five. Nine of the eleven trials used the MRC definition of chronic bronchitis, and nearly all the patients in the studies were smokers.

Efficacy

In nine trials, no exacerbation of bronchitis occurred in 351/723 (49%) of patient taking N-acetylcysteine and 229/733 (31%) of patients taking placebo (Figure 1). The relative benefit was 1.6 (95% confidence interval 1.4 to 1.8) and the number needed to treat to prevent an exacerbation was 5.8 (4.5 to 8.1).

Figure 1: Effect of N-acetylcysteine on exacerbations in chronic bronchitis





In five trials, 286/466 (61%) of patients rated their treatment as good or excellent with N-acetylcysteine compared with 160/462 (35%) with placebo (Figure 2). The relative benefit was 1.8 (95% confidence interval 1.5 to 2.1) and the number needed to treat for one extra patient to rate their treatment good or excellent was 3.7 (3.0 to 4.9).

Figure 2: Effect of N-acetylcysteine on patient self-report of improvement in chronic bronchitis





Harm

In six trials, dyspepsia, heartburn or diarrhoea occurred in 68/665 (10.2%) of patients using N-acetylcysteine and 73/671 (10.9%) of those using placebo. The relative risk was 1.0 (0.7 to 1.3).

In 10 trials, withdrawal because of adverse effects occurred in 79/1207 (6.5%) of patients using N-acetylcysteine and 87/1234 (7.1%) of those using placebo. The relative risk was 0.9 (0.7 to 1.2).

Comment

This is another study from an experienced EBM group in Switzerland. The study of N-acetylcysteine complements a Cochrane review [2], but gives more useful results on treatment benefit and harm. The bottom line is that N-acetylcysteine benefits patients with chronic bronchitis without causing any treatment-related harm.

This could well be a useful training paper for those learning or teaching critical appraisal skills. The paper examines the sensitivity of the results to known sources of bias (Bandolier 80) and examines how trial results are affected by different parameters, like duration, or cumulative dose of N-acetylcysteine. It is a thoughtful piece of work, and the sensitivity analyses done serve only to strengthen the conclusions about the efficacy of N-acetylcysteine.

But what about the issue of clinical relevance? This again is dissected, but with a less clear cut answer. Obviously patients are doing better. Obviously patients without exacerbation consume fewer healthcare resources. There is a hint that hospital admissions are less. But maybe we lack all the tools to construct a clear-cut health economic case.

The trouble is that health economics is an inexact science, and Bandolier often feels that the less exact it tries to be the more useful it is. Health workers who deal with patients with chronic bronchitis could easily produce a simple model that would tell us whether treating patients with chronic bronchitis with N-acetylcysteine was not only good for patients, but good for healthcare systems.

Don't forget the sting in the tail. The anglophones were wrong. The evidence for N-acetylcysteine efficacy is good. Another problem for EU harmonisation.

References:

  1. C Stey et al. The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review. European Respiratory Journal 2000 16: 253-262.
  2. PJ Poole, PN Black. Mucolytic agents for chronic bronchitis. The Cochrane Library Issue 4, 2000. Oxford, Update Software.


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