Search

Aclidinium bromide is a novel, long-acting, muscarinic antagonist in phase III development for the maintenance treatment of COPD. This phase IIb study investigated the efficacy and safety of aclidinium for the treatment of moderate to severe COPD to establish the optimal dose for phase III studies. A total of 464 patients with moderate to severe stable COPD were randomised to double-blind, once-daily treatment with aclidinium (25, 50, 100, 200, or 400microg), placebo, or open-label tiotropium (18microg) for 4 weeks. Spirometric measurements were performed at 22-24h after the first dose and then at weekly intervals, and from 0.5 to 6h post-dose on day 1 and day 29. Compared with placebo, aclidinium 200microg and 400microg significantly increased trough FEV(1) on day 29 versus baseline. During the first 6h post-dose, the bronchodilatory effect of aclidinium (all doses) on day 1 was comparable to that on day 29. Time to peak FEV(1) was 3h for aclidinium 100-400microg. Aclidinium was well tolerated, with no dose-dependent effect on ECG, laboratory parameters, or adverse events. The incidence of AEs was generally comparable to placebo. Aclidinium produced sustained bronchodilation over 24h and was well tolerated during this short-term study. Based on these data, aclidinium 200microg was selected as the investigational dose for future clinical trials in COPD., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The Inhaled Steroids in Obstructive Lung Disease (ISOLDE) study was a trial that randomised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years. We aimed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-randomisation. Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics. Deaths were classified according to the trial protocol. In the subsample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted, the factors associated with observed higher mortality (p<0.05) were male gender, older age and more severe COPD. Causes of death were; 107 (52%) respiratory, 38 (18%) cardiac, 29 (14%) lung cancer, 16 (8%) other cancer and 16 (8%) other causes. The percentage of respiratory-related deaths increased during the follow-up period; from 46% within the three-year trial, to 48% after 3-6 years, 57% after 6-9 years, and 60% after 9-13 years of follow-up (p for trend<0.05). We conclude that participants' survival is poor (only 44% in the 13 years after the ISOLDE trial), and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD.

The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Background: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1)., Methods: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking., Results: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers., Conclusions: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.

Objectives: To explore the cost-effectiveness of fluticasone propionate (FP) for the treatment of chronic obstructive pulmonary disease (COPD), we estimated costs and quality-adjusted life-years (QALYs) over 3 years, based on an economic appraisal of a previously reported clinical trial (Inhaled Steroids in Obstructive Lung Disease in Europe [ISOLDE])., Methods: Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study. The SF-36-based utility scores for quality of life were used to calculate QALYs. A combined imputation and bootstrapping procedure was employed to handle missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period. The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty., Results: Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 (95% confidence interval [CI]-0.01 to 0.15) life-years was observed. In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95% CI 619-1338 sterling pound) with an additional effect of 0.11 QALYs (CI 0.04-0.20). Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained (6900 sterling pound to infinity) and 9500 sterling pound per QALY gained (CI 4300-26,500 sterling pound) were generated that include uncertainty due to the imputation process. An alternative imputation approach did not materially affect these estimates., Conclusions: Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP. This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP. Based on these data, the inhaled corticosteroid FP appears cost-effective for the treatment of COPD. Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health (TORCH) study reports, a large randomized controlled trial powered to detect mortality changes associated with the use of FP alone, or in combination with salmeterol, which is also collecting resource use and utility data suitable for estimating cost-effectiveness.

Symptoms of obstructive lung disease in domestic cleaners have been related to the use of bleach and other irritant cleaning products. The short-term effects of cleaning exposures on respiratory symptoms and peak expiratory flow (PEF) were investigated in domestic cleaners with respiratory disorders. In a panel study, 43 female domestic cleaners with a recent history of asthma and/or chronic bronchitis completed a 2-week diary, collecting information on respiratory symptoms, PEF and cleaning exposures. Mixed regression models were used to assess daily changes in symptoms and PEF associated with specific cleaning exposures. The probability of having work-related asthma was individually assessed by a computerised diagnostic system and an occupational asthma expert. Lower respiratory tract symptoms were more common on working days and were predominantly associated with exposure to diluted bleach, degreasing sprays/atomisers and air fresheners. Associations with upper respiratory tract symptoms and PEF were less apparent. Eleven (30%) subjects scored positively for work-related asthma. It is concluded that exposure to certain irritant cleaning products aggravates lower respiratory tract symptoms in female domestic cleaners with asthma or chronic bronchitis.

Prevention of exacerbations of chronic obstructive pulmonary disease (COPD) can involve removing the cause or reducing the patient's vulnerability to the cause. This article addresses the following issues: What is the problem during an exacerbation, what are the causes of an exacerbation, what can prevent exacerbations, and who are we? The difference between a patient with COPD during an exacerbation and after recovery is small. It is unlikely that patients with early COPD experience less exposure to exacerbation causes than those with severe disease; it is just that the consequences are more severe for those with severe disease. Interventions that produce small absolute benefits can therefore have a disproportionately large effect on exacerbation reduction. Recognized causes include season, cold weather, pollution events, bacterial infection, viral infection, and treatment withdrawal. Countries with warmer climates have much larger mortality in cold weather than those with colder climates. Reducing exacerbations in more temperate climates may be altered as much by changes in clothing and bedroom heating as by changes in treatment. Taking more exercise in cold weather may be the underlying reason for the reduction of exacerbations after pulmonary rehabilitation. Influenza vaccination reduces influenza severity and reduces transmission from health care workers to patients. There are a number of pharmacologic interventions shown to reduce (the effect of) exacerbations, including inhaled corticosteroids, long-acting beta-agonists, long-acting anticholinergics, mucolytics, and perhaps antibiotics that reduce Haemophilus carriage. The effect of the bronchodilators is additive to inhaled corticosteroids; how far the other interventions are complementary is unclear. So far, we have had a very medical response to COPD exacerbations. Altering social and behavioral aspects is likely to be complementary.

Background: Clinical studies suggest that inhaled corticosteroids reduce exacerbations and improve health status in chronic obstructive pulmonary disease (COPD). However, their effect on mortality is unknown., Methods: A pooled analysis, based on intention to treat, of individual patient data from seven randomised trials (involving 5085 patients) was performed in which the effects of inhaled corticosteroids and placebo were compared over at least 12 months in patients with stable COPD. The end point was all-cause mortality., Results: Overall, 4% of the participants died during a mean follow up period of 26 months. Inhaled corticosteroids reduced all-cause mortality by about 25% relative to placebo. Stratification by individual trials and adjustments for age, sex, baseline post-bronchodilator percentage predicted forced expiratory volume in 1 second, smoking status, and body mass index did not materially change the results (adjusted hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.55 to 0.96). Although there was considerable overlap between subgroups in terms of effect sizes, the beneficial effect was especially noticeable in women (adjusted HR 0.46; 95% CI 0.24 to 0.91) and former smokers (adjusted HR 0.60; 95% CI 0.39 to 0.93)., Conclusions: Inhaled corticosteroids reduce all-cause mortality in COPD. Further studies are required to determine whether the survival benefits persist beyond 2-3 years.

Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (<1.65 exacerbations x yr(-1)) and frequent (>1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.

Objectives: To investigate the determinants of patient withdrawal from our study, and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD., Design: A double-blind, placebo-controlled, randomized trial., Setting: Eighteen outpatient centers in the United Kingdom., Participants: Seven hundred fifty-one patients with stable COPD defined clinically and as baseline postbronchodilator FEV(1) > or = 0.8 L and < 85% predicted, FEV(1)/FVC ratio < 70%, and FEV(1) change after albuterol < 10% of predicted., Intervention: Random assignment of either 500 microg bid of inhaled fluticasone propionate (FP) using a spacer device or an identical placebo inhaler. Treatment was continued for 3 years or until patients withdrew from follow-up., Measurements and Results: Postbronchodilator FEV(1) was measured on three occasions before randomization and every 3 months thereafter. Health status was assessed by the disease-specific St. George Respiratory Questionnaire (SGRQ) and the modified short-form 36 questionnaire (SF-36) at baseline and every 6 months. Three hundred thirty-nine patients withdrew, of whom 156 patients received FP. Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol (69 patients in the FP group withdrew due to respiratory symptoms, compared with 93 patients in the placebo group). This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1) was < 50% predicted. Patients withdrawing had a significantly more rapid decline in health status, measured by both the SGRQ and the SF-36 (p < 0.001). Those withdrawing from the placebo group had a more rapid decline in FEV(1) and more exacerbations than the FP-treated groups. Baseline FEV(1) was lower in dropouts than in patients completing the study receiving placebo, but there was no difference between the respective groups receiving FP., Conclusions: Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function. Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point.

Background: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV(1)) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV(1), health status, or number of exacerbations during placebo or fluticasone propionate treatment., Methods: Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV(1) after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV(1) and health status during the 3 years of the study., Results: The post-bronchodilator FEV(1) increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV(1) after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV(1) after prednisolone and the response to inhaled bronchodilators, baseline FEV(1), atopic status, age, or sex. The response to prednisolone, however expressed, was unrelated to the subsequent change in FEV(1) over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent prednisolone response. The significant effect of treatment on decline in health status was not predicted by the prednisolone response., Conclusion: Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV(1) response to prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.

Background: A limited or absent bronchodilator response is used to classify chronic obstructive pulmonary disease (COPD) and can determine the treatment offered. The reliability of the recommended response criteria and their relationship to disease progression has not been established., Methods: 660 patients meeting European Respiratory Society (ERS) diagnostic criteria for irreversible COPD were studied. Spirometric parameters were measured on three occasions before and after salbutamol and ipratropium bromide sequentially or in combination over 2 months. Responses were classified using the American Thoracic Society/GOLD (ATS) and ERS criteria. Patients were followed for 3 years with post-bronchodilator FEV(1) and exacerbation history recorded 3 monthly and health status 6 monthly., Results: FEV(1) increased significantly with each bronchodilator, a response that was normally distributed. Mean post-bronchodilator FEV(1) was reproducible between visits (intraclass correlation 0.93). The absolute change in FEV(1) was independent of the pre-bronchodilator value but the percentage change correlated with pre-bronchodilator FEV(1) (r=-0.44; p<0.0001). Using ATS criteria, 52.1% of patients changed responder status between visits compared with 38.2% using ERS criteria. Smoking status, atopy, and withdrawing inhaled corticosteroids were unrelated to bronchodilator response, as was the rate of decline in FEV(1), decline in health status, and exacerbation rate., Conclusion: In moderate to severe COPD bronchodilator responsiveness is a continuous variable. Classifying patients as "responders" and "non-responders" can be misleading and does not predict disease progression.

Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with worse health and increased healthcare utilisation. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study in COPD showed a 26% reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate (FP) compared to placebo, but did not indicate which patients showed greatest benefit. In this study the patients were stratified into mild and moderate-to-severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second (FEV1) 50% predicted, and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined. There were 391 (195 FP) patients with mild COPD and 359 (180 FP) patients with moderate-to-severe disease. The exacerbation rate was highly skewed in mild disease, but more normally distributed in moderate-to-severe disease. FP reduced the overall exacerbation rate in moderate-to-severe disease (FP median rate 1.47 yr(-1), placebo 1.75 yr(-1)), but not in mild disease (FP 0.67 yr(-1), placebo 0.92 yr(-1)). FP use was associated with fewer patients with > or = 1 exacerbation x yr(-1) being treated with oral corticosteroids (mild: FP 8%, placebo 16%; moderate-to-severe: FP 17%, placebo 30%). Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second <50% predicted. These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate-to-severe chronic obstructive pulmonary disease who experience recurrent exacerbations.

Chronic obstructive pulmonary disease (COPD) is irreversible and causes a progressive reduction in physical functioning. There is evidence that emotional distress contributes to loss of function and that improvements may be obtained via psychologically based interventions to alleviate anxiety and panic. This systematic review examined the most effective interventions to date. A literature search revealed 25 studies; these were assessed using standardised criteria for inclusion and quality. Six randomised, controlled trials fulfilled the criteria, but the variety of methods, interventions and measures prevented the use of a meta-analysis. Two studies were unpublished doctoral theses, four were published studies. All of the studies had one or more deficiencies; failure to measure or report lung function, large variation in attrition, lack of blinding in assessment of treatment outcome, lack of use of standardised anxiety measures. Description of the intervention was not always sufficient to allow replication. There were no trials of interventions aimed at reducing panic. No study was adequately designed to provide an assessment of psychological intervention aimed at anxiety in COPD. Secondary outcomes included impacts on breathlessness, disability and quality of life. It can be concluded that currently there is insufficient research of quality on which to base recommendations for effective interventions for anxiety and panic in COPD. Future research should tie the design of evaluation to interventions based on theories of the relationship between dyspnoea and anxiety.