Role of mucolytic agents in the treatment of chronic obstasctive pulmonary disease
(COPD) remains controversial. In some European countries
mucolytics are widely used, as in other countries (Britain, U.S.,
Australia), they are considered inefficient.
N-acetylcysteine (N-AC) refers to the mucolytic dasgs, as well as
has anti-inflammatory and antioxidant effects. Stey C. et al .
was conducted meta-analysis of studies evaluating the effectiveness of N-AC in the reception
mouth in patients with COPD. The main results, the impact
N-AC on the clinical symptoms, the frequency of exacerbations, as well as side effects.
Material and methods
Cistematichesky search terms " N-acetylcysteine "," NAC "," Fluimucil ",
" bronchitis "and combinations of these terms was held in the databases (Medline, Embase,
Cochrane Library), without language restrictions. For the analysis, we selected randomized
studies in which the N-AC compared with placebo or no treatment group
.
Relative benefit and relative risk were calculated on the basis of 95%
confidence interval (95% CI). used as indicator of "number needed
to treat" (NNTT) - the number of patients who need to be disinfected N-AC to
a positive effect (eg, lack of exacerbations) in addition
in one patient, compared with a group of placebo.
Results
As a result, Search only found 39 studies, 11 of them,
published between 1976 and 1994, were eligible for inclusion
(the others were out of control, or did not contain relevant data on the effects of
N-AC ingestion ). In all 11 studies in total
2540 patients were randomized to N-AC or a placebo.
for analysis were available data in 2011 patients (79% of total), of which 996 men were
N -AC, and 1015 - a placebo. On average, in one study, N-AC took 91 patients
(from 10 to 258). In all studies, except three, were used
placebo pills and N-AC, which are identical to shape, appearance and taste.
N-AC in all the papers given by mouth two or three times a day (400 or 600
mg / day). Timing of treatment were as follows: 4 weeks ( in one small study), 12
weeks (1 study), 20 weeks (1 study), 22 weeks (1 study), 24 weeks
(6 studies), 23-32 weeks (1 study).
Characteristics of patients
All patients - adults with chronic bronchitis (COPD according to the modern
terminology) of these smokers (including smoking in
history) in the different studies was from 72 to 100%.
precisely define levels of risk was not possible because data from different studies
risk factors it was difficult to generalize. For example, as a factor
risk in one study presented only previous hospitalization.
Four studies did not report other risk factors - the average number of
exacerbations during the previous year. As a result of the other 7 studies, it
ranged from 1 to 3 (two of them in the experimental subgroup of exacerbations wasmore
three per year).
Another indicator of risk may be data of respiratory function (ERF) .
However, two studies are not reported any of the LF, nor on the number of exacerbations
before the study began, in a third report the average number of exacerbations per
previous year, but no data ERF. The results of two studies, the average
forced expiratory volume in 1 second (FEV1) was <50% predicted
values.
Preventing exacerbations
exacerbation was defined according to clinical symptoms (increased cough
, gnoynosti sputum and / or shortness of breath). Data on the exacerbation were available in 9
from 11 studies: report no exacerbations for 12-24 weeks
total of 1456 patients. In all studies, the percentage of patients without
exacerbations in the group of N-AC was higher than in the placebo group. This difference reached statistical significance
in the two largest studies (48% of the total number of patients
). The efficiency of treatment duration or
total dose of N-AC has not been proved.
After combining data from all studies in which information was available about
exacerbations, a statistically significant difference between the N-D and placebo.
have 351 of 723 patients (48.5%) treated with N-AC in the study period was not
exacerbation in the placebo group there was no relapse in 229 of 733 patients (31,2%).
relative advantage in the application of N-AC was 1.56 (95% CI 1,37-1,77); NNTT
for the prevention of exacerbations in 1 patient was 5.8 (95% CI 4,5-8,1).
Only one study reported the frequency of hospital admissions because of worsening
. When using N-AC had to be hospitalized four of 258 patients
(1,6%) during the 24-week study period, while placebo -
9 of 268 (3.4%). The difference is not statistically significant: the relative benefit
0 , 47 (95% CI 0,16-1,42), NNTT 55 (95% CI 23-121).
Self patients
In five studies (n = 928) patients evaluated the effectiveness of treatment.
for analysis were combined data on patients reported improvement in their well-being
. When using N-AC 286 of 466 patients (61.4%) reported
improving their condition, while using the placebo - 160 of 462 (34,6%);
difference in favor of N-AC statistically significant. The relative benefit for
using the N-AC was 1.78 (95% CI 1,54-2,05); NNTT 3,7 (95% CI 3,0-4,9).
Side Effects
In 6 studies (n = 1336) to report information about adverse side effects on the
zheludochno_kishechnogo (GI) tract. When using N-AC 68
of 665 patients (10.2%) complained of indigestion, diarrhea or heartburn
compared with 73 of 671 (10.9%) in the control group. The relative risk when applying N-AC
was 0.96 (95% CI 0,70-1,30), ie, N-AC were not significantly increased the frequency of adverse events
from the digestive tract.
10 studies (n = 2441) contained data on the disposal of research iz_za
unwanted side effects. For this reason, participation in the study
stopped 79 of 1,207 patients (6.5%) treated with N-AC and 87 of 1234 patients
(7,1%) in the placebo group. The relative risk for retirement while taking N-AC was 0,92
(95% CI 0,69-1,23; difference not significant).
Other Endpoints
In five studies presented data on changes in FEV1 during the study.
In one study 4_nedelnom In patients with severe COPD recorded
statistically significant improvement in FEV1 in the treatment of N-AC - 25 to 30% due
(with placebo improvement was not). In another,moreprolonged
(24 weeks) study in patients with mild COPD was a statistically significant improvement in FEV1
(from 2.16 to 2.25 liters) while taking N-AC, in the placebo group
this effect was not observed. The authors of that study concluded that the effect
too small to be clinically significant. In the other three studies
N-AC treatment did not affect the FEV1.
talk
main conclusion of this meta-analysis is that the treatment of chronic bronchitis
oral N-AC ismoreeffective than placebo, while
as safe. Appointment of N-AC (400-600 mg / day for 12-24 weeks) 100
patients with chronic bronchitis can prevent aggravation of the 17
patients in whom it would arise in the case of placebo (NNTT 5,8).
In addition, treatment of N -AC leads to an improvement of an additional 26 patients
(which would not have occurred with placebo) (NNTT 3,8).
No differences were found between the N-D and placebo frequency of adverse events
from the digestive tract and the frequency of termination of their admission because of adverse reactions.
Thus, based on data from this systematic review can
conclude that taking N-AC for 3-6 months has a beneficial effect
in patients with chronic bronchitis. It remains unclear how
achieved this beneficial effect. pathogenesis of COPD is associated with oxidant stress
. N-AC, as tiolosoderzhaschim compound can act as a
anti-oxidant, contributing to production of glutathione - an important element of pulmonary
antioxidant protection. It is also assumed that the N-AC may affect
ability of bacteria to adhere, but the question of the role of these mechanisms of action of N-AC in
discussed the review not considered. However, you must answer questions about the reliability of the results
this meta-analysis and their clinical significance.
Threat meta-analysis is biased. It is obvious that the inclusion in the meta-analysis
inaccurate data leads to inaccurate conclusions. The danger lies in the
overestimation of treatment results. Thus, it is necessary to provide analysis
only reliable data.
There are several causes of bias in clinical research:
public purpose of treatment or failure to comply, blinded study, small
sample size, poor quality of research, in the case of meta-analysis - language
restrictions and registration re-publication. This meta-analysis was conducted
systematic search without language restrictions, we considered only the data
randomized controlled trials from the analysis were excluded
repeated publication. Thus, the probability of selection bias was
small. Most of the studies used placebo tablets indistinguishable
and N-AC. For a critical analysis confirmed acceptable methodological quality of original research
. But concern the high number of drop-outs
in some studies. Most of the drop-out study
(166 of 539 patients) was associated with undesirable side effects (outside
depending on the group - N-AC or placebo). Since effectiveness analysis
were not available data on dropout patients, we can not exclude the possibility
relationship between the increased likelihood of side effects and inadequate efficacy
N-AC. There remain several unresolved issues that may be useful in
planning of future research. First, although it was
attempt to divide patients according to level of risk due to heterogeneity
source data it was impossible to draw a conclusion about the effectiveness of N-AC in patients with various
risk of exacerbation and with varying degrees of airflow obstasction.
Secondly, the clinical significance requires clarification
prevent exacerbations. Role of exacerbations as a factor in accelerating the long-term deterioration
parameters of ERF, is not certain: one study revealed a
dependence, while three prospective studies the presence of such links does not
confirmed. Exacerbations may lead to frequent hospitalizations, which
significantly increase the cost of treatment, and are a predictor of adverse outcome
COPD. Only in One study reported
frequency of hospitalizations due to exacerbation: 3,4 and 1,6% for placebo or
N-AC, respectively. In this figure NNTT suggests that for
prevent one hospitalization the patient should treat N-AC 55
patients. Although this result is statistically not reliable, it has potentially
value. The problem is that the probability of admission is low, and for
identify statistically significant effect of N-AC requires large-scale
studies (> 2500 patients) or meta-analysis of data from several smaller studies
. In addition to assessing the economic effect of preventing
hospitalization interest influence N-AC on the duration of temporary disability
and cost of concomitant therapy.
Third, with regard to clinical appropriateness is important to note
that the maximum duration of the study was only 6 months. In
during this period was not obtained evidence of any impact
duration of the study or the total dose of N-AC on the effectiveness of treatment,
and no increased risk of adverse effects of dasgs.
However, as a prophylactic measure for patients may have to take N-AC
permanently or on At least every winter. This dictates the need for
study as favorable, and adverse effects of regular treatment
N-AC over a longer time.
Finally, variability touted in various study endpoints
says uncertainty scientists about what the result
most informative in these clinical conditions. Thus, not all studies
rated prevent exacerbations. In addition, there is no evidence that the beneficial effects
N-AC is associated with significant changes in the parameters of ERF,
which may be a surrogate marker for the effectiveness of mucolytics in COPD.
According to the authors, in this clinical context, improvement of health of patients
may be an important end result. feel better during
receiving N-AC in 61.4% of patients compared with 34.6% among patients receiving placebo
. But it is not known, which means "improvement of symptoms for
everyday life of the patient suffering from COPD while no one study
not analyze the quality of life. One can only assume that the "improvement of symptoms
" is an indicator of greater satisfaction and higher quality of life
.
Conclusion
Based on a systematic review of controlled studies Stey
C. et al. concluded that oral N-acetylcysteine for 3-6 months
patients suffering from chronic bronchitis, is well tolerated,
accompanied by a statistically significant reduction in the risk of exacerbations and a significant decrease in
bronchitis symptoms.