Oral Fabrol (oral N-acetyl-cysteine) in chronic bronchitis

Five hundred and twenty-six patients suffering from chronic bronchitis were randomized 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.     

N-isobutyrylcysteine, a donor of systemic thiols, does not reduce the exacerbation rate in chronic bronchitis.

N-isobutyrylcysteine (NIC), a new thiol compound that is not rapidly hydrolysed to give higher levels of free thiols in the body than N-acetylcysteine (NAC), was used to test if the effect of NAC on exacerbations in chronic bronchitis was an effect of the unhydrolysed thiol compound. Smokers or exsmokers with chronic bronchitis forced expiratory volume in one second (FEV1) >40% and reversibility < or = 10% predicted were treated with oral NIC 300 mg b.i.d. or placebo for 24 weeks. Steroids, NAC, antibiotics, and nonsteroid anti-inflammatory drugs use were restricted. Exacerbations were recorded by a respiratory symptom diary card and the time to onset of the first exacerbation after the start of treatment was measured using life-table analysis. Spirometry was performed at each visit. Six hundred and thirty-seven patients were randomized to treatment with NIC (n=316) or placebo (n=321). NIC did not prolong the time to first exacerbation (life-table analysis, p=0.59) and no increase in FEV1 or forced vital capacity was observed. Altered taste perception, taste loss and anosmia occurred more often in the NIC group (p<0.001). In conclusion, N-isobutyrylcysteine, a N-acetylcysteine-like drug with a greater bioavailability has, contrary to N-acetylcysteine, no effect on exacerbations in chronic bronchitis. This suggests that the effect of N-acetylcysteine on exacerbations in chronic bronchitis is not due to the relatively low free thiol levels (other than glutathione) produced by N-acetylcysteine therapy.     

Double-blind trial RU 41740 vs. placebo: immunological and clinical effects in a group of patients with chronic bronchitis

A double-blind trail was performed to investigate the effects of RU 41740, a glycoprotein extract from Klebsiella pneumoniae, on host defenses and its efficacy in reducing the number of exacerbation in 29 evaluable patients with chronic bronchitis, out of 36 patients who entered the study. The drug enhanced the phagocytosis indexes of both polymorphonuclear and mononuclear phagocytes. Increased candidacidal activity of monocytes was also observed. These effects, already detectable after one course of therapy and during the entire period of treatment, were no longer detectable when tested 6 months after the end of treatment. A significantly (p less than 0.05) larger number of patients in the treated group than in the placebo group had no exacerbations during drug administration (0-3 months). Moreover, patients treated with RU 41740 had significantly fewer and shorter episodes of acute exacerbation. The positive decreases in these two parameters persisted throughout the follow-up.     

N-acetylcysteine reduces the exacerbation rate in patients with moderate to severe COPD

OBJECTIVE: This study was performed to confirm the efficacy of a 6-month therapy with a formulation of N-acetylcysteine (NAC; 600 mg/day p.o.) on frequency and severity of exacerbations in patients suffering from chronic obstructive pulmonary disease (COPD). METHODS: One hundred sixty-nine patients attending five Italian centres were recruited in an open, randomized, controlled study. The patients were randomly allocated to standard therapy plus NAC 600 mg once a day or standard therapy alone over a 6-month period. At baseline, medical history was evaluated, and physical examination was performed; occurrence and severity of exacerbations and side effects of NAC were analyzed after 3 and 6 months. RESULTS: The results showed a decreased number of exacerbations (by 41%) in the group of patients treated with NAC and standard treatment: 46 patients had at least one exacerbation as compared with 63 patients of the group treated with standard therapy alone. Also the number of the patients with two or more exacerbations was lower in the NAC group (26%) than in the standard-therapy group (49%). The number of sick days was less (82) in the NAC group as compared with the standard-therapy group (155). There was a small but significant improvement in FEV(1) and MEF(50) in the NAC group. NAC once a day was well tolerated. There were no differences in the number of side effects reported in both groups. CONCLUSIONS: These data confirm results of previous studies which reported a reduction in the number of exacerbations in patients having moderate to severe COPD treated with the antioxidant NAC. Further, the once-daily formulation is well tolerated and is likely to improve patient compliance with the prescribed regimen. Copyright Copyright 1999 S. Karger AG, Basel     

The effect of oral N-acetylcysteine in chronic bronchitis: a quantitative systematic review.

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. A systematic search (Medline, Embase, Cochrane Library, bibliographies, no language restriction) for published randomized trials comparing oral NAC with placebo in patients with chronic bronchitis was performed. Dichotomous data on prevention of exacerbation, improvement of symptoms and adverse effects were extracted from original reports. The relative benefit and number-needed-to-treat were calculated for both individual trials and combined data. Thirty-nine trials were retrieved; eleven (2,011 analysed patients), published 1976-1994, were regarded as relevant and valid according to preset criteria. In nine studies, 351 of 723 (48.5%) patients receiving NAC had no exacerbation compared with 229 of 733 (31.2%) patients receiving placebo (relative benefit 1.56 (95% confidence interval (CI) 1.37-1.77), number-needed-to-treat 5.8 (95% CI 4.5-8.1). There was no evidence of any effect of study period (12-24 weeks) or cumulative dose of NAC on efficacy. In five trials, 286 of 466 (61.4%) patients receiving NAC reported improvement of their symptoms compared with 160 of 462 (34.6%) patients receiving placebo (relative benefit 1.78 (95% CI 1.54-2.05), number-needed-to-treat 3.7 (95% CI 3.0-4.9)). With NAC, 68 of 666 (10.2%) patients reported gastrointestinal adverse effects compared with 73 of 671 (10.9%) taking placebo. With NAC, 79 of 1,207 (6.5%) patients withdrew from the study due to adverse effects, compared with 87 of 1,234 (7.1%) receiving placebo. In conclusion, with treatment periods of approximately 12-24 weeks, oral N-acetylcysteine reduces the risk of exacerbations and improves symptoms in patients with chronic bronchitis compared with placebo, without increasing the risk of adverse effects. Whether this benefit is sufficient to justify the routine and long-term use of N-acetylcysteine in all patients with chronic bronchitis should be addressed in further studies and cost-effectiveness analyses.     

Oral immunotherapy of chronic bronchitis: a double-blind placebo-controlled multicentre study

104 patients with chronic bronchitis were treated under randomized double-blind conditions with either Broncho-Vaxom (BV) or a placebo over a period of 6 consecutive months. The beneficial effect of BV was manifested by a statistically significant reduction in the duration of acute episodes and of fever (p less than 0.001) with respect to the placebo group. The consumption of antibiotics dropped significantly in the BV group (p less than 0.05) but not in the placebo group. The serum IgA levels increased in the BV group and the difference with the placebo group was statistically significant (p less than 0.05) from the 3rd month onwards. In the patients with bronchitic exacerbations during the trial, T-lymphocyte counts increased steadily under BV therapy until 3 months after the exacerbation (p less than 0.05), but not under the placebo. BV was generally well tolerated with the exception of 1 patient who reported nausea and upper abdominal pain. In their assessment of the overall therapeutic effect, the physician judged BV to be significantly superior (p less than 0.001) to the placebo as regards both the curative and prophylactic efficacy.     

Double-blind study of Biostim in the prevention of superinfection in patients with chronic bronchopathy

In a multicenter trial conducted with patients suffering from chronic bronchopathy, Biostim, an immunomodulating compound of biological origin has been studied using the double-blind placebo-controlled method for prevention of respiratory tract infections. One hundred and ten patients from 10 french pneumology health centers entered the study. The treatment was administered at random in three sequences of 8 days a month for 3 months (2 mg/day the first month, 1 mg/day the second and third months). Patients were separated into 2 groups regarding severity of the disease: group I (non complicated chronic bronchitis); group II (obstructive chronic bronchitis with or without respiratory failure). Patients were examined during 6 months with a monthly appraisal of number, duration and treatment clinically defined infectious episodes. The study of propensity to infections with respect to severity of the disease in patients given placebo showed a significantly lower number of infectious episodes in group I when compared to group II. In the group I (patients suffering from simple chronic bronchitis), no significant difference could be noted between placebo and Biostim but, at all events, the low frequency of episodes makes it difficult to evidence a protective effect in such a group. In contrast, with patients presenting a high infectious risk (group II), one can observe in Biostim treated patients compared with placebo group a significant decrease of infectious episodes and a larger number of patients standing free of episodes throughout the whole period of trial. Tolerance to Biostim has revealed itself satisfactory.     

Effect of OM-85 BV on reducing bronchiectasis exacerbation in Chinese patients: the iPROBE study

BackgroundBronchiectasis is characterized by recurrent infectious exacerbations. No existing data inform preventive strategy for exacerbations beyond chronic macrolides. OM-85 BV, an immunostimulant, has been shown to prevent recurrent respiratory infections. We initiated this 1-year, multi-centered, double-blind, and controlled trial to investigate the PReventive effect of OM-85 BV on Bronchiectasis Exacerbations in Chinese patients (iPROBE).MethodsPatients with bronchiectasis aged 18 to 75 years, having at least one exacerbation in the past year, were randomized to receive, in addition to any respiratory medications, two courses of 7 mg of OM-85 BV or matching placebo (one capsule orally per day for 10 days a month) for 3 consecutive months, followed by 3 months without treatment. The primary outcomes included the number of acute infectious exacerbations and the time to first exacerbation. Secondary endpoints included patient-reported respiratory outcomes. Safety measures were also assessed.ResultsAmong the 196 participants, 99 were in the OM-85 BV group and 97 in the placebo group. At week 52, the mean number of acute exacerbations per patient was equal to 0.98 and 0.75, respectively, in the two groups (P=0.14). Difference in the time to first pulmonary exacerbation was not statistically significant (P=0.11). There was no statistically significant difference in any secondary end-points. The safety profile in the two arms was good and the majority of adverse events were mild.ConclusionsOM-85 BV did not demonstrate protection in decreasing pulmonary exacerbations of bronchiectasis in this trial performed in Chinese patients. It had good safety profile.     

Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease

BACKGROUND: Interventions against acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are increasingly called for to reduce morbidity, mortality and costs. OM-85, a detoxified immunoactive bacterial extract, has been shown to prevent recurrent exacerbations of bronchitis and COPD. OBJECTIVES: It was the aim of this study to demonstrate the protective effect of OM-85 against recurrent bronchitic exacerbations in patients with chronic bronchitis or mild COPD. The primary end point was the mean rate of AEs occurring within the study period. METHODS: This double-blind multi-centre study enrolled adult outpatients>40 years old of both sexes with a history of chronic bronchitis or mild COPD at the time of an AE. The treatment consisted of one capsule of OM-85 or placebo per day for 30 days, followed by three 10-day courses for months 3, 4 and 5, with a 6-month study duration and monthly control visits. RESULTS: One hundred and forty-two patients were treated with OM-85 and 131 received placebo. By the end of the treatment period, the mean number of AEs in the OM-85 group was 0.61 per patient versus 0.86 per patient in the placebo group (-29%; p=0.03). The difference between treatments was most notable in patients with a history of current or past smoking (-40%; p<0.01). No serious adverse events were attributed to the medication and no significant laboratory changes were reported. CONCLUSIONS: OM-85 significantly reduced the frequency of AEs in patients with a history of chronic bronchitis and mild COPD and was well tolerated. This study confirms the findings of previous trials conducted in elderly patients with chronic bronchitis or COPD.     

PEEP-masks in patients with severe obstructive pulmonary disease: a negative report

Positive pressure during expiration by face masks applied by the patient has gained wide acceptance in the treatment of chronic bronchitis, but the efficacy is still unproven. The effect of 6 months of treatment with PEEP-masks (positive end-expiratory pressure) was therefore studied in 47 patients with severe irreversible obstructive pulmonary disease (forced expiratory volume in one second (FEV1) about 1 l), and mucus hypersecretion. Patients were double-blindly randomized to at least 45 min daily treatment with PEEP-masks with either 10 or 0 cm water pressure. After 6 months of treatment, no statistical difference was found between the two groups in change of median values (month 6 - month 0) of FEV1, forced vital capacity (FVC), arterial oxygen tension (PaO2), amount of sputum or dyspnoea. Median values of arterial carbon dioxide tension (PaCO2) decreased significantly (0.03 kPa) in the placebo group. Cough intensity and dyspnoea during walking on staircases improved significantly in the placebo group. No difference among groups was found in number of days bedridden, hospitalized, number of exacerbations or antibiotic consumption. We conclude, that the use of PEEP-masks in these patients is without clinical documentation and cannot be recommended.     

Inhibitory effect of N-acetylcysteine on adherence of Streptococcus pneumoniae and Haemophilus influenzae to human oropharyngeal epithelial cells in vitro

BACKGROUND: Bacterial adherence to mucosal and epithelial cell structures is of importance for the persistence of bacteria in the airways. Cigarette smoking and chronic bronchitis are associated with increased bacterial adherence. N-Acetylcysteine (NAC) medication reduces the number of infectious exacerbations in patients with chronic bronchitis, and NAC medication has been associated with low intrabronchial bacterial numbers. OBJECTIVE: We investigated whether NAC influences bacterial adherence as a possible mechanism behind its clinical effects. METHODS: Highly adhering test strains of Streptococcus pneumoniae and Haemophilus influenzae were used to investigate the influence of four pharmacological compounds on adherence to oropharyngeal epithelial cells in vitro. Adhesion assays were performed both during short-term exposure to, as well as after long-time incubation with, NAC, lidocaine, hydrocortisone and terbutaline at concentrations not inhibiting bacterial growth. RESULTS: Only NAC showed a significant inhibitory effect on adhesion of H. influenzae during short-term incubation. After long-term incubation, both NAC and hydrocortisone inhibited bacterial adhesion for both strains in a dose-dependent manner. When NAC's effect on three different strains of S. pneumoniae and four strains of H. influenzae was studied, inhibition of bacterial adhesion was found for three strains of each species. CONCLUSIONS: NAC lowers bacterial adhesion in vitro to oropharyngeal epithelial cells in doses equivalent to that is being used clinically. This effect might be a contributory mechanism behind the reduction of infectious exacerbations in chronic bronchitis patients.     

Reduction in the incidence of acute bronchitis by an oral Haemophilus influenzae vaccine in patients with chronic bronchitis in the highlands of Papua New Guinea

Following the administration of a standardized questionnaire, 62 adult patients with chronic bronchitis were enrolled into a double-blind controlled trial of an oral killed Haemophilus influenzae vaccine in the highlands of Papua New Guinea. A 3-day course of vaccine or placebo was given monthly for 3 consecutive months. Participants were monitored weekly over 12 months for acute exacerbations; early morning sputum specimens were collected monthly and during acute exacerbations. Density of colonization by H. influenzae and H. parainfluenzae was determined by standard quantitative and semiquantitative techniques, and the latter method (quadrant score) was used to determine the density of growth of pneumococci. A total of 30 patients received vaccine and 32 placebo. The incidence rate of acute bronchitis in the vaccine group (0.011 episodes/person-weeks) was significantly lower than that in the placebo group (0.021 episodes/person-weeks), but there was no difference between the two groups in the incidence rates of more severe disease. Vaccine efficacy was maximal at times of peak incidence of disease. There was no evidence of a decline in vaccine efficacy for acute bronchitis over the 12-month follow-up period. The number of viable H. influenzae in the sputum declined in both vaccine and placebo groups over the 12-month follow-up period. The average concentration of H. influenzae in the vaccine group fell below that in the placebo group within 1 to 2 months after first immunization and remained so for 12 months, although the difference between the two groups narrowed during the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Die Langzeitbehandlung der chronischen Bronchitis mit dem Breitband-Chemotherapeuticum „Bactrim“

In a double blind trial 22 patients, suffering from chronic obstructive bronchitis, were administered “Bactrim” and 15 patients received placebo for a period of 9 months. All patients received two tablets daily. No side effects of the chemo-therapy were noticed. Airway resistance, interthoracic gas-volume and the volume of the sputum did not change in comparison with the placebo group. The frequency of exacerbations was lower in the Bactrim group than in the placebo group. Bactrim was found to be a valuable complement in the therapy of patients suffering from chronic obstructive bronchitis with a high frequency of exacerbations.     

The effect of tiotropium on exacerbations and airflow in patients with COPD.

This randomised, double-blind, parallel-group, 1-yr study compared the effect of tiotropium 18 microg once daily (n=500) and placebo (n=510) on exacerbations, associated health resource use (HRU) and airflow limitation in chronic obstructive pulmonary disease (COPD) patients. The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40, the mean weekly morning peak expiratory flow (PEF) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second (FEV1) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days, reduced the proportion of patients experiencing more than one exacerbation by 17%, and decreased the number of exacerbations by 35% and exacerbation days by 37% versus placebo. Tiotropium also decreased HRU versus placebo, as indicated by the significant reductions in the use of concomitant respiratory medications, antibiotics and oral steroids, and the number of unscheduled physician contacts. Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study. At the end of the study, tiotropium significantly improved trough (pre-dose) FEV1, forced vital capacity, slow vital capacity and inspiratory capacity versus placebo. In conclusion, tiotropium reduced exacerbations and associated health resource use, and improved airflow over 1 yr in chronic obstructive pulmonary disease patients.     

Low-dose budesonide with the addition of an increased dose during exacerbations is effective in long-term asthma control. On behalf of the Italian Study Group

OBJECTIVES: This study was designed to compare the effects of a 6-month treatment with budesonide 100 microg bid (low dose) and 400 microg bid (standard reference dose) in controlling symptoms and lung function in a group of asthmatics with moderate asthma (baseline FEV(1) > or = 50% and < or = 90% of predicted values) previously treated with inhaled beclomethasone dipropionate (500 to 1,000 microg/d). Moreover, we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide. METHODS: After a 2-week run-in period and 1-month treatment with a high dose of budesonide (800 microg bid), 213 patients with moderate asthma were assigned to randomized treatments. Daily treatment included budesonide (bid) plus an additional treatment in case of exacerbation (qid for 7 days). Treatments were as follows: budesonide 400 microg plus placebo (group 1); budesonide 100 microg plus budesonide 200 microg (group 2); and budesonide 100 microg plus placebo (group 3). Symptoms and a peak expiratory flow (PEF) diary were recorded and lung function was measured each month. An exacerbation was defined as a decrease in PEF > 30% below baseline values on 2 consecutive days. RESULTS: We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms. Moreover, symptoms were under control in all treatment groups throughout the study period. Similarly, lung function improved and remained stable, and no relevant differences between groups were observed. In each treatment group, the majority of patients had no exacerbations. In patients treated with the standard budesonide dose (group 1), the number of exacerbations and days with exacerbations were significantly lower than in group 3 (intention-to-treat analysis). Additionally, patients treated with low budesonide dose plus budesonide (group 2) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 (per-protocol analysis). CONCLUSIONS: This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide, a low dose of budesonide (200 microg/d) is as effective as the standard dose (800 microg/d) in the control of symptoms and lung function over a period of several months. Furthermore, results showed that the addition of inhaled budesonide (800 microg/d) at onset of an asthmatic exacerbation has a beneficial clinical effect.     

Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study

The aim of this double-blind single center study (the COPE study) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate (FP) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease. After 4 months of treatment with FP (1,000 microg/day), 244 patients were randomized to either continue FP or to receive placebo for 6 months: 123 patients continued FP (FP group), and 121 received placebo (placebo group). In the FP group, 58 (47%) patients developed at least one exacerbation compared with 69 (57%) in the placebo group. The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 (95% confidence interval [CI] 1.1-2.1). In the placebo group 26 patients (21.5%) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients (4.9%) in the FP group (relative risk = 4.4; 95% CI 1.9-10.3). Over a 6-month period, a significant difference in favor of the FP group was observed in the total score (+2.48 95% CI 0.37-4.58), activity domain (+4.64 95% CI 1.60-7.68), and symptom domain (+4.58 95% CI 1.05-8.10) of the St. George's Respiratory Questionnaire. This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life.     

Infections with viruses and Mycoplasma pneumoniae during exacerbations of chronic bronchitis.

The association of viral and Mycoplasma pneumoniae infections with acute exacerbations of chronic bronchitis was studied by serologic or isolation techniques in 46 adult men during the five years from 1964 through 1968. Serologic evidence of viral or M. pneumoniae infection was detected in 25% of 166 episodes of exacerbation and 14% of 138 remission periods (P = 0.02). Influenza A virus, parainfluenza virus type 3, and coronavirus OC43 predominated; infections with other viruses were infrequent. Infection with M. pneumoniae was detected serologically in four patients, but this organism was never isolated from sputum specimens. Rhinoviruses were isolated from frozen-stored sputum specimens in in 2.7% of the episodes of exacerbation and from 0.55% of the remission intervals (P not significant). These data suggest that although exacerbations of chronic bronchitis may be accompanied by viral and M. pneumoniae infections, patients with chronic bronchitis also acquire such infections without a worsening of their respiratory status.     

Preventing exacerbations of chronic bronchitis and COPD: therapeutic potential of mucolytic agents

It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure. A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3-6 months to achieve one less exacerbation over that time. Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year. How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects. They do not appear to affect the decline in lung function that occurs in COPD. The treatment appears to be without any adverse effects, apart from the need to take oral medication daily. Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year. This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective. Those with more frequent and severe exacerbations appear to have the most to gain.     

Effect of Aclidinium Bromide on Exacerbations in Patients with Moderate-to-Severe COPD: A Pooled Analysis of Five Phase III,Randomized, Placebo-Controlled Studies

We investigated the effect of the long-acting muscarinic antagonist aclidinium bromide on chronic obstructive pulmonary disease (COPD) exacerbations by pooling data from five randomized, placebo-controlled, parallel-group Phase III studies of 3–6 months’ duration. Data were pooled from the aclidinium 400 μg twice-daily (BID) and placebo arms (N = 2,521) and stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) group (A, B, C and D). Results showed that fewer patients experienced ≥1 exacerbation with aclidinium (any severity: 12.5%; moderate to severe: 10.9%) compared with placebo (any severity: 15.7%; moderate to severe: 13.3%) and the odds of experiencing ≥1 exacerbation of any severity were reduced in patients receiving aclidinium (odds ratio = 0.78, p = 0.039). Furthermore, aclidinium reduced the rate of exacerbations compared with placebo (any severity: rate ratio = 0.79, p = 0.026; moderate to severe: 0.80, p = 0.044). The time to first exacerbation of any severity was delayed with aclidinium compared with placebo (hazard ratio = 0.79, p = 0.026) and there was a numerical delay in time to first moderate-to-severe exacerbation. Finally, the effects of aclidinium on exacerbations versus placebo were greater in patients in GOLD Groups B and D; however, it is of note that only 10.7% of patients were classified in Group A or C. In summary, the results indicate that aclidinium 400 μg BID reduces the frequency of COPD exacerbations compared with placebo and that these effects are greater in symptomatic patients.     

Preventing Exacerbations of Chronic Bronchitis and COPD

It is important to find interventions that will reduce the frequency and severity of exacerbations of COPD, because of their effect on morbidity and healthcare expenditure. A Cochrane systematic review included 23 studies that had evaluated the effects of treatment with mucolytic agents in patients with chronic bronchitis or COPD. Mucolytic treatment was associated with a significant reduction of 0.79 exacerbations per patient per year compared with placebo, a 29% decrease. Patients who received treatment with mucolytic agents were twice as likely to remain exacerbation-free in the study period than if they had received placebo, with six patients needing regular treatment with mucolytic agents for 3–6 months to achieve one less exacerbation over that time. Treatment with mucolytic agents resulted in nearly 7 days less illness per patient per year.How mucolytic agents work is unknown, although they may reduce exacerbations by altering mucus production, antioxidation, or antibacterial or immunostimulatory effects. They do not appear to affect the decline in lung function that occurs in COPD. The treatment appears to be without any adverse effects, apart from the need to take oral medication daily. Cost-effectiveness analysis suggests that the point at which the costs of treatment and non-treatment were equal was 1.2 less exacerbations per year. This is higher than the effect observed in the Cochrane review, suggesting that treating everyone with COPD with mucolytic agents would not be cost effective. Those with more frequent and severe exacerbations appear to have the most to gain.