Pma Calverley

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

The Standards for the Diagnosis and Treatment of Patients with COPD document 2004 updates the position papers on chronic obstructive pulmonary disease (COPD) published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 1995 1, 2. Both societies felt the need to update the previous documents due to the following. 1) The prevalence and overall importance of COPD as a health problem is increasing. 2) There have been enough advances in the field to require an update, especially adapted to the particular needs of the ATS/ERS constituency. 3) It allows for the creation of a “live” modular document based on the web; it should provide healthcare professionals and patients with a user friendly and reliable authoritative source of information. 4) The care of COPD should be comprehensive, is often multidisciplinary and rapidly changing. 5) Both the ATS and the ERS acknowledge the recent dissemination of the Global Initiative of Obstructive Lung Disease (GOLD) 3 as a major worldwide contribution to the battle against COPD. However, some specific requirements of the members of both societies require adaptation of the broad GOLD initiative. Those requirements include specific recommendations on oxygen therapy, pulmonary rehabilitation, noninvasive ventilation, surgery in and for COPD, sleep, air travel, and end-of-life. In addition, special emphasis has been placed on issues related to the habit of smoking and its control. ### Goals and objectives The main goals of the updated document are to improve the quality of care provided to patients with COPD and to develop the project using a disease-oriented approach. To achieve these goals, both organisations have developed a modular electronic web-based document with two components. 1) A component for health professionals that intends to: raise awareness of COPD; inform on the latest advances in the overall pathogenesis, diagnosis, monitoring and management of COPD; and …

Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial

Abstract Objectives: To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. Design: Double blind, placebo controlled study. Setting: Eighteen UK hospitals. Participants: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV1) 50% of predicted normal. Interventions: Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo. Main outcome measures: Efficacy measures: rate of decline in FEV1 after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. Results: There was no significant difference in the annual rate of decline in FEV1 (P=0.16). Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). Conclusions: Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1. Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.

Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 µg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 µg, budesonide 400 µg, formoterol 9 µg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St Georges Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (−7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort®) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.

Bronchodilator reversibility testing in chronic obstructive pulmonary disease

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 FEV1 and exacerbation history recorded 3 monthly and health status 6 monthly. Results: FEV1 increased significantly with each bronchodilator, a response that was normally distributed. Mean post-bronchodilator FEV1 was reproducible between visits (intraclass correlation 0.93). The absolute change in FEV1 was independent of the pre-bronchodilator value but the percentage change correlated with pre-bronchodilator FEV1 (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 FEV1, 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.

Impact of preventing exacerbations on deterioration of health status in COPD

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 Georges 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·yr−1) and frequent (>1.65 exacerbations·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.

Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease

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.

Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results

Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 μg, fluticasone propionate (FP) 500 μg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age ≥55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg·m−2. No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.

Cardiovascular and metabolic effects of CPAP in obese males with OSA

Obstructive sleep apnoea is associated with increased blood pressure and other features of the metabolic syndrome. The aim of the present study was to determine the relative effectiveness of continuous positive airway pressure (CPAP) in modifying these outcomes. A randomised placebo-controlled blinded crossover trial comparing cardiovascular and metabolic outcomes after 6 weeks of therapeutic and sham CPAP was performed in 34 CPAP-naïve patients (mean±sd body mass and respiratory disturbance indices were 36.1±7.6 and 39.7±13.8, respectively). Mean waking systolic and diastolic blood pressure fell by 6.7 and 4.9 mmHg, respectively, when compared with sham CPAP. No change was observed in glucose, lipids, insulin resistance or the proportion of patients with metabolic syndrome. In CPAP-compliant patients the fall in blood pressure was greater and the baroreceptor sensitivity improved significantly but no metabolic variable changed. In obese Caucasians with untreated obstructive sleep apnoea, continuous positive airways pressure can improve baroreceptor responsiveness and reduce waking blood pressure within 6 weeks, but this treatment period was insufficient to modify insulin resistance or change the metabolic profile. The mechanisms underlying this difference in the time course of blood pressure and metabolic response to continuous positive airway pressure in obstructive sleep apnoea requires further exploration.

Inflammatory Biomarkers Improve Clinical Prediction of Mortality in Chronic Obstructive Pulmonary Disease

RATIONALE Accurate prediction of mortality helps select patients for interventions aimed at improving outcome. OBJECTIVES Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy. METHODS A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers. MEASUREMENTS AND MAIN RESULTS At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers. CONCLUSIONS The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT00292552).

Disease severity and the effect of fluticasone propionate on chronic obstructive pulmonary disease exacerbations

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 ≥1 exacerbation·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.