Oral Fabrol (oral N-acetyl-cysteine) in chronic bronchitis. The importance of quality of primary studies in producing unbiased systematic reviews. The National Mucolytic Study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Using Numerical Results from Systematic Reviews in Clinical Practice Irish General Practice Study of Acetylcysteine (Fabrol) in Chronic Bronchitis Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments) Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. Oral N-acetylcysteine and exacerbation rates in patients with chronic bronchitis and severe airways obstruction. British Thoracic Society Research Committee. Oral acetylcysteine reduces exacerbation rate in chronic bronchitis: report of a trial organized by the Swedish Society for Pulmonary Diseases. A controlled trial of intermittent oral acetylcysteine in the long-term treatment of chronic bronchitis Orally administered N-acetylcysteine may improve general well-being in patients with mild chronic bronchitis. Efficacy and Tolerability of Oral Acetylcysteine (Fabrol®) in Chronic Bronchitis: A Double-Blind Placebo Controlled Study Beta blockade during and after myocardial infarction: an overview of the randomized trials.
Five hundred and twenty-six patients suffering from chronic bronchitis were r and omized to receive either N-acetylcysteine ( NAC ) or placebo during a 6-month period . The aim was to compare the number of acute exacerbations in the two groups . General practitioners were asked to enter patients with a diagnosis of chronic bronchitis , based on the MRC criteria . We failed to find any statistically significant difference in the number of exacerbations between the two treatment groups although there was a slight trend towards improvement in the NAC group during the first 3 months of the trial . The tolerability was similar for both treatments . Patients taking NAC showed a reduction in number of days on which they were incapacitated and this result was statistically significant BACKGROUND Traditional and largely qualitative review s of evidence are now giving way to much more structured systematic overviews that use a quantitative method to calculate the overall effect of treatment . The latter approach is dependent on the quality of primary studies , which may introduce bias if they are of poor method ologic quality . OBJECTIVE To test the hypothesis that the inclusion of poor- quality trials in meta-analyses would bias the conclusions and produce incorrect estimates of treatment effect . METHODS An overview of r and omized trials of antiestrogen therapy in subfertile men with oligospermia was performed to test the hypothesis . Data sources included online search ing of MEDLINE and Science Citation Index data bases between 1966 and 1994 , scanning the bibliography of known primary studies and review articles , and contacting experts in the field . After independent , blind assessment , nine of 149 originally identified studies met the inclusion criteria and were selected . We assessed study quality independently . Outcome data from each study were pooled and statistically summarized . RESULTS There was a marginal improvement in pregnancy rate with antiestrogen treatment ( odds ratio , 1.6 ; 95 % confidence interval , 0.9 to 2.6 ) . Sensitivity analyses on the basis of method ologic quality demonstrated that poor- quality studies produced a positive effect with treatment , whereas no benefit was observed with high- quality studies . CONCLUSION The results of a meta- analysis are influenced by the quality of the primary studies included . Method ologically , poor studies tend to exaggerate the overall estimate of treatment effect and may lead to incorrect inferences Seventy-four pulmonologists and one allergist were recruited to assess the efficacy and safety of iodinated glycerol ( Organidin ) , 60 mg qid , vs placebo in patients with stable chronic obstructive bronchitis in a r and omized , double-blind , placebo-controlled , parallel design . A total of 361 patients ( 180 to iodinated glycerol and 181 to placebo ) who complained of cough and difficulty bringing up sputum entered the eight-week study . Evaluations were based upon eight primary symptom efficacy parameters ( cough frequency , cough severity , chest discomfort , dyspnea , ease in bringing up sputum , patient and physician global assessment s , and a derived patients ' global assessment ) , and six secondary parameters ( frequency of aerosol bronchodilator use , incidence and duration of acute exacerbations , frequency of concomitant medication use , incidences of adverse experiences and dropouts ) . Cough frequency , cough severity , chest discomfort , patients ' ease in bringing up sputum , patients ' overall condition , and a derived subject global assessment were significantly ( p less than 0.05 ) improved by iodinated glycerol as compared with placebo within eight weeks of treatment . Dyspnea showed a trend toward improvement and the physicians ' global evaluation showed no significant difference between groups . Similar findings were noted in a subgroup analysis of moderately-to-severely affected patients . The mean duration ( days ) of acute exacerbations and number of dropouts attributable to adverse experiences were significantly less ( p less than 0.05 ) in the iodinated glycerol group . ( ABSTRACT TRUNCATED AT 250 WORDS As professionals , we want to use the best treatments ; as patients , we want to be given them . Knowing whether an intervention works ( or does not work ) is fundamental to clinical decision making . However , clinical decision making involves more than simply taking published results of research directly to the bedside . Physicians need to consider how similar their patients are to those in the published studies , to take the values and preferences of their patients into account , and to consider their own experience with a given test or treatment . Evidence from clinical research is becoming increasingly important in medical- practice decisions as more and better evidence is published . But when is the evidence strong enough to justify changing a practice ? Individual studies that involve only small numbers of patients may have results that are distorted by the r and om play of chance and thus lead to less than optimal decisions . As is clear from other papers in this series , systematic review s identify , critically appraise , and review all the relevant studies on a clinical question and are more likely to give a valid answer . They use explicit methods and quality st and ards to reduce bias . Their results are the closest we can come to reaching the truth given our current state of knowledge . The questions about an intervention that a systematic review should answer are the following : 1 . Does it work ? 2 . If it works , how well does it work in general and compared with placebo , no treatment , or other interventions that are currently in use ? 3 . Is it safe ? 4 . Will it be safe and effective for my patients ? Whereas the critical appraisal and qualitative synthesis provided by review articles can be interpreted directly , the numerical products of quantitative review s can be more difficult to underst and and apply in daily clinical practice . This paper provides guidance on how to interpret the numerical and statistical results of systematic review s , translate these results into more underst and able terms , and apply them directly to individual patients . Many of these principles can also be used to interpret the numerical results of individual clinical studies . They are particularly relevant to systematic review s , however , because such review s contain more information than do primary studies and often exert greater influence than do individual studies . Making Sense of the Numerical Results of Clinical Studies Although the results of clinical studies can be expressed in intuitively meaningful ways , such results do not always easily translate into clinical decision making . For example , results are frequently expressed in terms of risk , which is an expression of the frequency of a given outcome . ( Risks are probabilities , which can vary between 0.0 and 1.0 . A probability of 0.0 means that the event will never happen , and a probability of 1.0 means that it always happens . ) Consider a hypothetical study of the recurrence of migraine headaches in a control group receiving placebo and a treatment group receiving a new antimigraine preparation , drug M ( a secondary prevention trial ) . Suppose that at the end of the trial , migraines recurred in 30 % of the control group ( the risk for recurrence was 0.30 ) but in only 5 % of the drug M group ( risk of 0.05 ) ( Table 1 ) . Table 1 . Numerical Expression of Hypothetical Clinical Trial Results The outcomes of the study are clear enough for the two groups when they are examined separately . But clinicians and patients are more interested in the comparative results , that is , the outcome in one group relative to the outcome in the other group . This overall ( comparative ) result can be expressed in various ways . For example , the relative risk , which is the risk in the treatment group relative to that in the control group , is simply the ratio of the risks in the two groups . In other words , relative risk is the risk in the treatment group divided by that in the control group , 0.05 0.30 , or 0.17 . The comparison can also be expressed as the reduction in relative risk , which is the ratio between the decrease in risk ( in the treatment group ) and the risk in the control group , 0.25 0.30 , or 0.83 ( Table 1 ) . ( The relative risk reduction can also be calculated as 1 relative risk ) . Although the clinical meaning of relative risk ( and relative risk reduction ) is reasonably clear , relative risk has the distinct disadvantage that a given value ( for example , 0.17 ) is the same whether the risk with treatment decreases from 0.80 to 0.14 , from 0.30 to 0.05 , from 0.001 to 0.00017 , and so forth . The clinical implication s of these changes clearly differ from one another enormously and depend on the specific disease and intervention . An important alternate expression of comparative results , therefore , is the absolute risk reduction . Absolute risk reduction is determined by subtracting the risk in one group from the risk in the other ( for example , the risk in the treatment group is subtracted from the risk in the placebo group ) . In the case of our migraine study , the absolute risk reduction would be 0.30 0.05 , which equals 0.25 , or 25 percentage points . In contrast , for a study in which the risk decreased from 0.001 to 0.00017 , the absolute risk reduction would be only 0.00083 , or 0.083 percentage points , which is a trivial change in comparison ( Table 1 ) . This arithmetic emphasizes the difficulty of expressing the results of clinical studies in meaningful ways . Relative risk and relative risk reduction clearly give a quantitative sense of the effects of an intervention in proportional terms but provide no clue about the size of an effect on an absolute scale . In contrast , although it tells less about proportional effects , absolute risk says a great deal about whether an effect is likely to be clinical ly meaningful . Despite this benefit , even absolute risk is problematic because it is a dimensionless , abstract number ; that is , it lacks a direct connection with the clinical situation in which the patient and physician exist . However , another way of expressing clinical research results can provide that clinical link : the number needed to treat ( NNT ) . Number Needed To Treat The NNT for a given therapy is simply the reciprocal of the absolute risk reduction for that treatment [ 1 , 2 ] . In the case of our hypothetical migraine study ( in which risk decreased from 0.30 without treatment with drug M to 0.05 with treatment with drug M , for a relative risk of 0.17 , a relative risk reduction of 0.83 , and an absolute risk reduction of 0.25 ) , the NNT would be 1 0.25 , or 4 . In concrete clinical terms , an NNT of 4 means that you would need to treat four patients with drug M to prevent migraine from recurring in one patient . To emphasize the difference between the concepts embodied in NNT and relative risk , recall the various situations mentioned above , in all of which the relative risk was 0.17 but in which the absolute risk decreased from 0.80 to 0.14 in one case and from 0.001 to 0.00017 in another . Note that the corresponding NNTs in these two other cases are 1.5 and 1204 , respectively : that is , you would need to treat 1.5 and 1204 patients to obtain a therapeutic result in these two situations compared with 4 patients with drug M ( Table 1 ) . The NNT can be calculated easily and kept as a single numerical reminder of the effectiveness ( or , as we will see , the potential for harm ) of a particular therapy . As we suggested , the NNT has the crucial advantage of direct applicability to clinical practice because it shows the effort that is required to achieve a particular therapeutic target . The NNT has the additional advantage that it can be applied to any beneficial outcome or any adverse event ( when it becomes the number needed to harm [ NNH ] ) . The concept of NNT always refers to a comparison group ( in which patients receive placebo , no treatment , or some other treatment ) , a particular treatment outcome , and a defined period of treatment . In other words , the NNT is the number of patients that you will need to treat with drug or treatment A to achieve an improvement in outcome compared with drug or treatment B for a treatment period of C weeks ( or other unit of time ) . To be fully specified , NNT and NNH must always specify the comparator , the therapeutic outcome , and the duration of treatment that is necessary to achieve the outcome . Important Qualities of the Number Needed To Treat The NNT is treatment specific . It describes the difference between treatment and control in achieving a particular clinical outcome . Table 2 shows NNTs from a selection of systematic review s and large r and omized , controlled trials . Table 2 . Numbers Needed To Treat from Systematic Review s and R and omized , Controlled Trials A very small NNT ( that is , one that approaches 1 ) means that a favorable outcome occurs in nearly every patient who receives the treatment and in few patients in a comparison group . Although NNTs close to 1 are theoretically possible , they are almost never found in practice . However , small NNTs do occur in some therapeutic trials , such as those comparing antibiotics with placebo in the eradication of Helicobacter pylori infection or those examining the use of insecticide for head lice ( Table 2 ) . An NNT of 2 or 3 indicates that a treatment is quite effective . In contrast , such prophylactic interventions as adding aspirin to streptokinase to reduce 5-week vascular mortality rates after myocardial infa rct ion may have NNTs as high as 20 to 40 and still be considered clinical ly effective . Limitations of the Number Needed To Treat Although NNTs are powerful instruments for interpreting clinical effects , they also have important limitations . First , an NNT is generally expressed as a single number , which is known as its point estimate . As with all experimental measurements , however , the true value of the NNT can be higher or lower than the point estimate determined through clinical studies . The 95 % CIs of the NNT are useful in this regard because they provide an indication that The results of this general practice study in 248 patients suggest that acetylcysteine ( Fabrol ) administered orally for 2 months to patients with chronic bronchitis effectively changes the viscosity and character of sputum with result ant ease of expectoration and cough severity . There was a notable improvement in associated abnormal physical signs such as the presence of rhonchi , crepitations and symptoms including dyspnoea at rest . Tolerability was good , with 77 % of patients experiencing no side-effects In order to describe the outcomes of patients hospitalized with an acute exacerbation of severe chronic obstructive pulmonary disease ( COPD ) and determine the relationship between patient characteristics and length of survival , we studied a prospect i ve cohort of 1,016 adult patients from five hospitals who were admitted with an exacerbation of COPD and a PaCO2 of 50 mm Hg or more . Patient characteristics and acute physiology were determined . Outcomes were evaluated over a 6 mo period . Although only 11 % of the patients died during the index hospital stay , the 60-d , 180-d , 1-yr , and 2-yr mortality was high ( 20 % , 33 % , 43 % , and 49 % , respectively ) . The median cost of the index hospital stay was $ 7,100 ( $ 4,100 to $ 16,000 ; interquartile range ) . The median length of the index hospital stay was 9 d ( 5 to 15 d ) . After discharge , 446 patients were readmitted 754 times in the next 6 mo . At 6 mo , only 26 % of the cohort were both alive and able to report a good , very good , or excellent quality of life . Survival time was independently related to severity of illness , body mass index ( BMI ) , age , prior functional status , PaO2/FI(O2 ) , congestive heart failure , serum albumin , and the presence of cor pulmonale . Patients and caregivers should be aware of the likelihood of poor outcomes following hospitalization for exacerbation of COPD associated with hypercarbia The clinical effect of N-acetylcysteine ( NAC ) controlled-release tablets , 300 mg b.i.d . , and placebo , in chronic bronchitis was investigated . The study was performed as a double-blind six month comparison between active drug and placebo in two parallel groups , with statistical evaluation after four and six months . The patients were chosen from nine centres . One hundred and sixteen out- patients were included and ninety one of them completed the six month study . The acetylcysteine-treated group had a significantly reduced number of sick-leave days caused by exacerbations of chronic bronchitis after the four winter months December-March compared with the control group ( NAC 173 , placebo 456 ) . The number of exacerbation days was also very much reduced , however , not significantly ( NAC 204 , placebo 399 ) . At the end of the six month trial , including also two spring months , the absolute numbers of sick-leave days and exacerbation days were still fewer in the acetylcysteine-treated group , ( NAC 260 , placebo 739 ) and ( NAC 378 , placebo 557 ) respectively . This study demonstrates a significant reduction in sick-leave days after four months of NAC-treatment . A constant tendency to reduction in the number of exacerbations and exacerbation days was also registered after four and six months . The differences in these parameters were , however , not statistically significant . This was probably due to the small number of patients participating The influence of oral N-acetylcysteine on the exacerbation rate in patients with chronic bronchitis and severe airways obstruction has been studied . Two hundred and forty four patients entered the study during October and November 1983 and took placebo sachets for a run in month . One hundred and eighty one who completed this month satisfactorily were r and omised to receive either active ( acetylcysteine 200 mg three times a day ) or matching placebo sachets for five months in a double blind parallel group study . The two groups were well matched . Patients kept detailed daily symptom diaries and were assessed monthly . At the end of the five months ' study the outcome in the group taking acetylcysteine appeared a little better , but the differences did not reach conventional levels of statistical significance for the mean ( SD ) number of exacerbations ( 2.1 ( 0.2 ) for acetylcysteine , 2.6 ( 0.2 ) for placebo ; p = 0.08 ) ; total days taking an antibiotic ( 13.5 ( 1.7 ) , 18.0 ( 2.8 ) ; p = 0.17 ) ; total days spent in bed ( 4.8 ( 0.8 ) , 5.1 ( 1.1 ) ; p = 0.9 ) ; number of withdrawals ( 13 ( 15 % ) , 20 ( 21 % ) ; p = 0.4 ) ; incidence of side effects ( which were few ) ; drug compliance ( which was good ) ; and the patients ' assessment of the treatment This multicentre trial was undertaken to confirm previous results indicating that long-term treatment with oral acetylcysteine reduces the exacerbation rate in patients with chronic bronchitis . Two hundred and eighty-five patients , smokers or ex-smokers , with chronic bronchitis started a pre-trial placebo-period of 1 month . After this run-in period 259 patients were included in the trial and r and omized into two parallel groups . The patients were treated in a double-blind way either with acetylcysteine 200 mg b.i.d . or placebo b.i.d . for 6 months . The trial was completed by 98 patients in the acetylcysteine group and by 105 patients in the placebo group . Initially , there were no significant differences between the groups . Twice weekly , the patients filled in a diary card concerning symptoms . The number of exacerbations was assessed from these cards and at visits 2 , 4 and 6 months after institution of therapy . The exacerbation rate was significantly lower in the acetylcysteine group in which 40 % of the patients remained free from exacerbations compared to 19 % in the placebo group . Sick-leave due to acute exacerbation was significantly less common in the acetylcysteine group . The drug was well tolerated Summary In 69 out- patients with chronic bronchitis in 6 centres the effects of acetylcysteine 600 mg daily , 3 days a week for 6 months , and a placebo have been compared in a double-blind controlled trial . Thirty-five patients were treated with the mucolytic and 34 with the dummy preparation .  In the former the clinical course of the chronic bronchitis improved to a greater extent and a significantly lower number of exacerbations was observed . The advantages of long-term oral treatment with the mucolytic in chronic bronchitis suggest that it may be useful as an alternative to long-term antibiotic prophylaxis , or to complement brief courses of antibiotics , in addition to the usual physiotherapy Oral N-acetylcysteine ( NAC ) exerts a beneficial action in chronic bronchitis by reducing the number of exacerbations . There have been few studies of the effect of NAC ( or of any other drug ) on general well-being in chronic bronchitis . We used an established psychiatric instrument ( General Health Question naire ; GHQ ) and a visual analogue scale ( VAS ) to measure well-being in a 22-week , placebo-controlled , double-blind , parallel-group study of NAC administered as sustained release tablets 600 mg b.i.d . , including during the winter months , to patients with mild chronic bronchitis . One hundred and fifty-three patients were accepted for r and omized treatment , 129 finished the study ( 59 NAC , 70 placebo ) , and well-being was measured in 105 ( 46 NAC , 59 placebo ) . The number of observed exacerbations was unexpectedly low in both groups . The number was lowest in the NAC group , however , the difference did not reach statistical significance in the present study ( P = 0.08 ) . There were no statistically significant differences between NAC and placebo in subjective symptom scores , FEV1 or FVC . The distribution of GHQ score at baseline was uneven , but NAC was significantly superior to placebo in terms of a favourable effect on GHQ score . GHQ score correlated with the number of exacerbations , and VAS correlated with GHQ score . This study therefore demonstrates the validity of measuring general well-being in patients with mild chronic bronchitis . Future studies of the treatment of chronic bronchitis should use a battery of more specifically adapted instruments which are now becoming available to measure well-being This multicentre , double-blind , placebo controlled , between-patient study in general practice in the United Kingdom examined the effect of oral N-acetylcysteine ( Fabrol ® ) on the symptomatology of patients with chronic bronchitis over a 3-month period . Although improvement in subjective symptoms ( sputum viscosity and character , difficulty in expectoration and cough severity ) occurred in both treatment groups over the trial period , improvements in difficulty in expectoration and cough severity were greater in patients receiving N-acetylcysteine compared to matching placebo . Trial medication was well tolerated , with a greater number of side-effects attributed to therapy occurring in patients receiving placebo Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews
The role of N-acetylcysteine ( NAC ) in the treatment of chronic bronchitis is unclear .
Since a number of studies have been published on this topic , a systematic review of published studies seems justified .