Bartolome R. Celli

A 4-year trial of Tiotropium in chronic obstructive pulmonary disease

BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy. METHODS In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. Georges Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality. RESULTS Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure. CONCLUSIONS In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)

Systemic manifestations and comorbidities of COPD.

Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the “spill-over” of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers. The role of gastric colonization

Gram-negative nosocomial pneumonia may result from retrograde colonization of the pharynx from the stomach, and this may be more likely when the gastric pH is relatively high. We studied the rate of nosocomial pneumonia among 130 patients given mechanical ventilation in an intensive care unit who were receiving as prophylaxis for stress ulcer either sucralfate (n = 61), which does not raise gastric pH, or conventional treatment with antacids, histamine type 2 (H2) blockers, or both (n = 69). At the time of randomization to treatment, the two groups were similar in age, underlying diseases, and severity of acute illness. Patients in the sucralfate group had a higher proportion of gastric aspirates with a pH less than or equal to 4 (P less than 0.001) and significantly lower concentrations of gram-negative bacilli (P less than 0.05) in gastric aspirates, pharyngeal swabs, and tracheal aspirates than did patients in the antacid-H2-blocker group. The rate of pneumonia was twice as high in the antacid-H2 group as in the sucralfate group (95 percent confidence interval, 0.89 to 4.58; P = 0.11). Gram-negative bacilli were isolated more frequently from the tracheal aspirates of patients with pneumonia who were receiving antacids or H2 blockers. Mortality rates were 1.6 times higher in the antacid-H2 group than in the sucralfate group (95 percent confidence interval, 0.99 to 2.50; P = 0.07). Although our results fell just short of statistical significance when they were analyzed according to intention to treat, they suggest that agents that elevate gastric pH increase the risk of nosocomial pneumonia in patients receiving ventilation by favoring gastric colonization with gram-negative bacilli. We conclude that in patients receiving mechanical ventilation, the use of a prophylactic agent against stress-ulcer bleeding that preserves the natural gastric acid barrier against bacterial overgrowth may be preferable to antacids and H2 blockers.

Characterisation of COPD heterogeneity in the ECLIPSE cohort

BackgroundChronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE).MethodsWe studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography.ResultsCOPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified.ConclusionsThe clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease.

Effect of Pharmacotherapy on Rate of Decline of Lung Function in Chronic Obstructive Pulmonary Disease Results from the TORCH Study

RATIONALE Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function. No drug has been shown conclusively to reduce this decline. OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health (TORCH) study, we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg, either component alone or placebo, on the rate of post-bronchodilator FEV(1) decline in patients with moderate or severe COPD. METHODS A randomized, double-blind, placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries. Of 6,112 patients from the efficacy population, 5,343 were included in this analysis. MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years. There were 26,539 on-treatment observations. The adjusted rate of decline in FEV(1) was 55 ml/year for placebo, 42 ml/year for salmeterol, 42 ml/year for fluticasone propionate, and 39 ml/year for salmeterol plus fluticasone propionate. Salmeterol plus fluticasone propionate reduced the rate of FEV(1) decline by 16 ml/year compared with placebo (95% confidence interval [CI], 7-25; P < 0.001). The difference was smaller for fluticasone propionate and salmeterol compared with placebo (13 ml/year; 95% CI, 5-22; P = 0.003). Rates of decline were similar among the active treatment arms. FEV(1) declined faster in current smokers and patients with a lower body mass index, and varied between world regions. Patients who exacerbated more frequently had a faster FEV(1) decline. CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate, or the components, reduces the rate of decline of FEV(1) in patients with moderate-to-severe COPD, thus slowing disease progression. Clinical trial (GSK Study Code SCO30003) registered with www.clinicaltrials.gov (NCT00268216).

Outcomes for COPD pharmacological trials: from lung function to biomarkers

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.

Changes in Forced Expiratory Volume in 1 Second over Time in COPD

BACKGROUND A key feature of chronic obstructive pulmonary disease (COPD) is an accelerated rate of decline in forced expiratory volume in 1 second (FEV(1)), but data on the variability and determinants of this change in patients who have established disease are scarce. METHODS We analyzed the changes in FEV(1) after administration of a bronchodilator over a 3-year period in 2163 patients. A random-coefficient model was used to evaluate possible predictors of both FEV(1) levels and their changes over time. RESULTS The mean (±SE) rate of change in FEV(1) was a decline of 33±2 ml per year, with significant variation among the patients studied. The between-patient standard deviation for the rate of decline was 59 ml per year. Over the 3-year study period, 38% of patients had an estimated decline in FEV(1) of more than 40 ml per year, 31% had a decline of 21 to 40 ml per year, 23% had a change in FEV(1) that ranged from a decrease of 20 ml per year to an increase of 20 ml per year, and 8% had an increase of more than 20 ml per year. The mean rate of decline in FEV(1) was 21±4 ml per year greater in current smokers than in current nonsmokers, 13±4 ml per year greater in patients with emphysema than in those without emphysema, and 17±4 ml per year greater in patients with bronchodilator reversibility than in those without reversibility. CONCLUSIONS The rate of change in FEV(1) among patients with COPD is highly variable, with increased rates of decline among current smokers, patients with bronchodilator reversibility, and patients with emphysema.

The 6‐min walk distance: change over time and value as a predictor of survival in severe COPD

The 6‐min walk distance (6MWD) is used to evaluate the functional capacity of patients with chronic obstructive pulmonary disease (COPD). The change in 6MWD over time and its correlation with changes in spirometry and survival are unclear. Patients (n=198) with severe COPD and 41 age-matched controls were followed for 2 yrs, and anthropometrics, spirometry, 6MWD and comorbidities were measured. The 6MWD decreased in the COPD group from 238±107 m to 218±112 m (−26±37 m·yr−1), and increased in the control group from 532±82 m to 549±86 m (12±25 m·yr−1). In both groups, there was a poor correlation with changes in forced expiratory volume in one second (FEV1). Nonsurvivors in the COPD group (42%) had a more pronounced change in the 6MWD (−40 versus −22 m·yr−1) but a similar change in FEV1 (118 versus 102 mL·yr−1). The 6MWD independently predicted survival, after accounting for age, body mass index, FEV1 and comorbidities. In severe chronic obstructive pulmonary disease, the 6‐min walk distance predicts mortality better than other traditional markers of disease severity. Its measurement is useful in the comprehensive evaluation of patients with severe disease.

Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype

Background Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552). Methods and Findings Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice. Conclusions Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.

C-reactive protein in patients with COPD, control smokers and non-smokers

Background: Patients with chronic obstructive pulmonary disease (COPD) have raised serum levels of C reactive protein (CRP). This may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as concomitant ischaemic heart disease (IHD) or smoking status. The aim of this study was to evaluate IHD and smoking as potential causes of raised CRP levels in COPD and to test the association between inhaled corticosteroid (ICS) use and serum CRP levels. Methods: Cross sectional analyses comparing cohorts of 88 patients with COPD, 33 smokers (S), and 38 non-smoker (NS) controls were performed. Clinical assessments included a complete medical history, pulmonary function, 6 minute walk test (6MWT), cardiopulmonary exercise test, and high sensitivity serum CRP measurements. Results: Serum CRP levels were significantly higher in patients with COPD (5.03 (1.51) mg/l) than in controls (adjusted odds ratio 9.51; 95% confidence interval 2.97 to 30.45) but were similar in the two control groups (S: 2.02 (1.04) mg/l; NS: 2.24 (1.04) mg/l). There was no clinical or exercise evidence of unstable IHD in any of the subjects. CRP levels were lower in COPD patients treated with ICS than in those not treated (3.7 (3.0) mg/l v 6.3 (3.6) mg/l); this association was confirmed in an adjusted regression model (p<0.05). Conclusion: CRP levels are raised in COPD patients without clinically relevant IHD and independent of cigarette smoking, and reduced in patients with COPD using ICS. CRP may be a systemic marker of the inflammatory process that occurs in patients with COPD.