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Background: Exacerbations are a defining outcome of chronic obstructive pulmonary disease (COPD). We evaluated the effect of tiotropium on COPD exacerbations and related hospitalizations among patients from the USA enrolled in clinical trials. Methods: Data were pooled from six randomized, double-blind, placebo-controlled trials (6 to≥12 months' duration) of tiotropium in patients with COPD. Exacerbations were defined retrospectively as an increase in or new onset of >1 respiratory symptom lasting for ≥ 3 days and requiring treatment with systemic corticosteroids and/or antibiotics. Time to first exacerbation or hospitalization and exacerbation rates were analyzed at 6 months, and at ≥1 year for studies1 year. Results: In total, 4355 patients (tiotropium, 2268, placebo, 2087; mean age 66.5 years; forced expiratory volume in 1 s [FEV1] 1.03 L [35.5% predicted]) were analyzed at 6 months and 2455 at 1 year (tiotropium 1317, placebo 1138; mean age 65.5 years; FEV1 1.03 L [37.0% predicted]). Tiotropium delayed time to first exacerbation or first hospitalized exacerbation at 6 months (hazard ratios [HRs], 0.80, 0.65, respectively; p < 0.001 vs placebo) and 1 year (HRs, 0.73 and 0.55; p < 0.001 vs placebo) and reduced exacerbation rates and hospitalization rates (6 months: HRs, 0.79, 0.64; 1 year: HRs, 0.78, 0.56, respectively; all p < 0.01 vs placebo). Tiotropium significantly reduced exacerbations, irrespective of inhaled corticosteroid use at baseline. Tiotropium was not associated with an increased risk of cardiac-related events. Conclusions: Tiotropium significantly reduced the risk and rates of exacerbations and hospitalizations among US patients with COPD. [ABSTRACT FROM AUTHOR]

Background: COPD is an independent risk factor for lung cancer, especially in patients with mild to moderate disease. Objective: To determine if performing lung cancer screening in GOLD 1 and 2 COPD patients, results in reduced lung cancer mortality. Methods: This study compared patients with mild to moderate COPD from 2 cohorts matched for age, gender, BMI, FEV1%, pack-yrs history and smoking status. The screening group (SG) had an annual low dose computed tomography (LDCT). The control group (CG) was prospectively followed with usual care. Lung cancer incidence and mortality densities were compared between groups. Results: From an initial sample of 410 (SG) and 735 (CG) patients we were able to match 333 patients from each group. At the same follow-up time lung cancer incidence density was 1.79/100 person-years in the SG and 4.14/100 person-years in the CG (p = 0.004). The most frequent histological type was adenocarcinoma in both SG and CG (65% and 46%, respectively), followed by squamous cell carcinoma (25% and 37%, respectively). Eighty percent of lung cancers in the SG (16/20) were diagnosed in stage I, and all of CG cancers (35/35) were in stage III or IV. Mortality incidence density from lung cancer (0.08 vs. 2.48/100 person-years, p < 0.001) was lower in the SG. Conclusions: This pilot study in patients with mild to moderate COPD suggests that screening with LDCT detects lung cancer in early stages, and could decrease lung cancer mortality in that high risk group. Appropriately designed studies should confirm these important findings. [ABSTRACT FROM AUTHOR]

Background: Observational and randomized studies have demonstrated that lung volume reduction surgery (LVRS) improves symptoms, lung function, and survival in selected patients with emphysema. In spite of an approximately 3.8 million patient prevalence of the disease in the US, only 119 LVRS procedures were performed nationwide under Medicare during 2008. In order to obtain evidence-based estimate on the size of the patient pool potentially suitable for LVRS, we analyzed the database from our clinical practice that is representative of a substantial segment of the general emphysema population. Methods: Our pulmonary function test laboratory database between 1996 and 2006 was searched for patients with stage III and IV global initiative for chronic obstructive lung disease (GOLD) who also had lung volumes and carbon monoxide diffusing capacity data. Patients without available chest computed tomographic scans (CT) or with primary diagnoses other than emphysema were excluded. The resultant emphysema cohort was screened using clinical inclusion and exclusion criteria adopted from the National Emphysema Treatment Trial. A suitable clinical profile combined with CT scan evidence of 40% or greater involvement of the lungs and predominantly upper lobe distribution of emphysema were regarded as favorable markers for LVRS. Results: Pulmonary function test criteria were met by 959 patients and CT scans were available in 588 patients, but 175 patients were excluded because of primary diagnoses other than emphysema. In the remaining 413 patients, 61 or 15% exhibited favorable clinical profiles and anatomy for LVRS. Conclusions: In a subset of patients that resembles a substantial segment of the general population with advanced emphysema, up to 15% appeared potential candidates for LVRS. Formation of a task force by relevant medical specialty and patient advocate organizations to address the apparent underutilization of LVRS is recommended. [ABSTRACT FROM AUTHOR]

Summary: Background: In COPD patients, hyperinflation impairs cardiac function. We examined whether lung deflation improves oxygen pulse, a surrogate marker of stroke volume. Methods: In 129 NETT patients with cardiopulmonary exercise testing (CPET) and arterial blood gases (ABG substudy), hyperinflation was assessed with residual volume to total lung capacity ratio (RV/TLC), and cardiac function with oxygen pulse (O2 pulse=VO2/HR) at baseline and 6 months. Medical and surgical patients were divided into “deflators” and “non-deflators” based on change in RV/TLC from baseline (∆RV/TLC). We defined deflation as the ∆RV/TLC experienced by 75% of surgical patients. We examined changes in O2 pulse at peak and similar (iso-work) exercise. Findings were validated in 718 patients who underwent CPET without ABGs. Results: In the ABG substudy, surgical and medical deflators improved their RV/TLC and peak O2 pulse (median ∆RV/TLC −18.0% vs. −9.3%, p =0.0003; median ∆O2 pulse 13.6% vs. 1.8%, p =0.12). Surgical deflators also improved iso-work O2 pulse (0.53mL/beat, p =0.04 at 20W). In the validation cohort, surgical deflators experienced a greater improvement in peak O2 pulse than medical deflators (mean 18.9% vs. 1.1%). In surgical deflators improvements in O2 pulse at rest and during unloaded pedaling (0.32mL/beat, p <0.0001 and 0.47mL/beat, p <0.0001, respectively) corresponded with significant reductions in HR and improvements in VO2. On multivariate analysis, deflators were 88% more likely than non-deflators to have an improvement in O2 pulse (OR 1.88, 95% CI 1.30–2.72, p =0.0008). Conclusion: In COPD, decreased hyperinflation through lung volume reduction is associated with improved O2 pulse. [Copyright &y& Elsevier]

Summary: Background: Chronic obstructive pulmonary disease (COPD) patients are thought to have limited bronchodilator response, determined by changes in forced expiratory volume in 1s (FEV1). In this study, we assessed bronchodilator response in patients with COPD using not only FEV1 but also changes in lung volume expressed as forced vital capacity (FVC) and inspiratory capacity (IC). We also evaluated the speed of onset of bronchodilation. Methods: Data were from 2 randomized, double-blind, placebo-controlled studies (6-months [NCT00206154]; 12-months [NCT00206167]) in patients with moderate to very severe COPD. Treatments: twice daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9μg, budesonide/formoterol pMDI 160/9μg, formoterol dry powder inhaler (DPI) 9μg, placebo. Results: The percentage of patients with FEV1 improvement (≥12% and ≥200mL; American Thoracic Society [ATS] criterion) was 34–39% post-albuterol (screening). On day of randomization (DOR), a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min: FEV1 (57–59%). Similar results were seen for IC (50–61%) and FVC (57–67%) using the same improvement criteria. The time to ≥15% FEV1 improvement on DOR was 5.0, 4.8, and 7.3min for budesonide/formoterol 320/9, budesonide/formoterol 160/9, and formoterol, respectively. Time to ≥15% FEV1 improvement was better maintained with budesonide/formoterol than formoterol at treatment end (6 and 12 months). Conclusions: Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment. Budesonide/formoterol pMDI also has a rapid (within 5min) onset of bronchodilation that is maintained over time compared with formoterol alone. [ABSTRACT FROM AUTHOR]

Summary: Rationale: COPD is a debilitating disease with increasing mortality worldwide. The BODE index evaluates disease severity and the St George’s Respiratory Questionnaire (SGRQ) measures health status. Objective: To identify the relationship between BODE index and the SGRQ and to test the predictive value of both tools against survival. Methods: Open cohort study of 1398 COPD patients (85% male) followed for up to 10 years. Measurements and main results: At the time of the inclusion, clinical data, forced spirometry and 6 min walking distance were determined and BODE index and SGRQ were calculated. Vital status and cause of death were documented at the end of follow-up. Results: The cohort’s mean of FEV1% predicted was 46 ± 18%, BODE index was 3.6 ± 2.5, and SGRQ% total score was 49 ± 20. The SGRQ scores increased progressively as severity of COPD increased by BODE quartiles. The correlation between SGRQ and BODE index was good (r = 0.58, p < 0.0001). Both tests correlated with COPD survival (BODE = −0.4 vs. SGRQ = −0.20, p < 0.0001). The area under the curve (AUC) for the BODE index was 0.77 vs. 0.66 for the SGRQ % total score (p < 0.001). Conclusions: Health status as measured by SGRQ worsens with disease severity evaluated by the BODE index. Both tools predict mortality and provide complimentary information in the evaluation of patients with COPD. [Copyright &y& Elsevier]

Summary: Background: The 6-min walking test (6MWT) is widely used to assess exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Given the prognostic significance of the 6MWT, it is important to identify why some COPD patients perform poorly in terms of this outcome. We aimed to identify clinical determinants of a poor 6-min walking distance (<350 m) in patients with COPD. Methods: 1795 individuals with a diagnosis of COPD underwent spirometry; bio-electrical impedance analysis; low-dose computed tomography scans of the chest; 6MWT; ATS-DLD co-morbidity questionnaire; Center for Epidemiologic Studies of Depression Scale; COPD-specific St Georges Respiratory Questionnaire; modified Medical Research Council (mMRC) dyspnea scale as part of the baseline assessment of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Results: Patients with COPD have significant differences in performance in the 6MWT even after stratification for GOLD stages. Moreover, severe airflow limitation by GOLD stage, degree of emphysema by CT, oxygen use during/after the 6MWT, presence of depressive symptoms and moderate to severe symptoms of dyspnea (mMRC grade ≥2) are significant clinical determinants of poor 6MWD performance (<350 m). Conclusions: The determinants of poor 6MWD are complex and depend on both physical (both pulmonary and non-pulmonary factors) and psychological factors as evaluated from a large multinational cohort of well-characterised patients with clinically stable moderate to very severe COPD. [Copyright &y& Elsevier]

Summary: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in adults. Although FEV1 remains the most important physiologic indicator of the severity of airflow obstruction in COPD, its predictive value for mortality is weak when it is higher than 50% of predicted. Furthermore, other easily obtainable clinical variables predict mortality better than the FEV1 in COPD patients with a wide range of airflow limitation. Chief among these predictors are functional dyspnea, exercise capacity, and the body mass index (BMI), although emerging research suggests a potential role for biomarker profiles in outcome predictions. The validated multidimensional BMI (B), degree of airflow obstruction as expressed by the FEV1 (O), dyspnea with the modified medical research council (D), and exercise (E) measured with the 6min walk or BODE index encompasses the predictive validity of the best of these variables into a single surrogate measure of disease severity and survival. This article reviews these predictors of mortality in COPD. [Copyright &y& Elsevier]

Summary: Objectives: This study assesses the power of the BODE index, a multidimensional grading system that predicts mortality, to predict subsequent exacerbations in patients with COPD. Design: Prospective cohort study. Patients and interventions: A total of 275 COPD patients were followed every 6 months up to 8 years (median of 5.1 years). Baseline clinical variables were recorded and the BODE index was calculated. We investigated the prognostic value of BODE quartiles (scores 0–2, 3–4, 5–6 and 7–10) for both the number and severity of exacerbations requiring ambulatory treatment, emergency room visit, or hospitalization. Results: The annual rate of COPD exacerbations was 1.95 (95% CI, 0.90–2.1). The mean time to a first exacerbation was inversely proportional to the worsening of the BODE quartiles (7.9 yrs, 5.7 yrs, 3.4 yrs and 1.3 yrs for BODE scores of 0–2, 3–4, 5–6 and 7–10, respectively). Similarly, the mean time to a first COPD emergency room visit was 6.7 yrs, 3.6 yrs, 2.0 yrs and 0.8 yrs for BODE quartiles (all p <0.05). Using ROC curves, the BODE index was a better predictor of exacerbation than the FEV1 alone (p <0.01). Conclusions: The BODE index is a better predictor of the number and severity of exacerbations in COPD than FEV1 alone. [Copyright &y& Elsevier]

Summary: The severity of chronic obstructive pulmonary disease (COPD) is currently assessed using a single physiological measurement, the forced expiratory volume in 1s (FEV1). COPD, however, has complex effects on other aspects of respiratory function, and in many patients is associated with important systemic changes. We hypothesized that a multidimensional staging system for COPD could provide a more complete assessment of the disease''s impact. We considered over 40 potential staging variables, evaluating them according to sensitivity to change, measured reproducibly, independence of the information they provide and prognostic value. We finally selected three: FEV1 (including arterial blood gas measurements when FEV1 falls below 35% predicted), Medical Research Council dyspnea scale and body mass index (BMI). Each measure correlates independently with prognosis in COPD, is supported by a significant body of literature and serves as a surrogate for other potentially important variables. We then used principal components analysis (PCA) to determine the degree of association between 30 of the potential variables measured in 813 stable COPD patients. Using PCA, six groups of measurements defined independent categories of patient information: pulmonary function (including FEV1), symptoms of cough and sputum, dyspnea, health status, bronchodilator reversibility and BMI. These include the three principal variables selected for the staging system. Although the staging boundaries were based on existing literature, they have proven useful in predicting survival. We conclude that a multidimensional grading system is useful to assess the impact of COPD. [Copyright &y& Elsevier]

Background: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB.Objective: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD).Methods: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age > 35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram''s staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7–10) and late (days 25–35) posttreatment visits.Results: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, −8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, −3.7to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, −6.6%; 95% CI, −25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram''s staining. Both treatments were well tolerated.Conclusions: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics. [Copyright &y& Elsevier]

Summary: Chronic obstructive pulmonary disease (COPD) ranks fourth as a cause of death in the United States, behind heart disease, cancer, and stroke. Additionally, since serious co-morbidities are often present in patients with COPD, many die from other diseases such as cardiac disease or cancer. Not surprisingly, multiple factors, reflective of both respiratory disease process and the substantial co-morbidity, predict survival in the disease. As might be expected, physiologic derangements such as airflow obstruction, hypoxemia, lung hyperinflation, and exercise capacity predict survival in COPD. Anemia, cachexia and reductions in lean body mass also relate to prognosis. Perhaps less recognized is the more recent documentation that more subjective assessments, such as dyspnea and health related quality of life, are also important predictors of survival. The integration of some of the most important of these variables may provide a more comprehensive evaluation of disease severity. For example, a validated multi-dimensional disease rating that includes the body mass index (B), degree of airflow obstruction (0), dyspnea (D), and exercise capacity (E) (BODE Index) is capable of predicting COPD-related hospitalization and mortality more than its individual components. [Copyright &y& Elsevier]

Background: Patients with chronic obstructive pulmonary disease (COPD) have increased risk of cardiovascular events.Objectives: This study evaluated the association between high-sensitivity cardiac troponin I concentration and cardiovascular events in patients with COPD and heightened cardiovascular risk.Methods: In a double-blind randomized controlled trial, 16,485 patients with COPD and cardiovascular disease or risk factors were randomized to once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or their combination. Plasma high-sensitivity cardiac troponin I concentrations were measured in a subgroup of 1,599 patients. Outcomes were on-treatment cardiovascular events and COPD exacerbations over a median of 18 months, and cardiovascular death over a median of 27 months.Results: Baseline plasma cardiac troponin I concentrations were above the limit of detection (1.2 ng/l) in 1,542 (96%) patients. Concentrations were unaffected by inhaled therapies at 3 months (p > 0.05). Compared with the lowest quintile (cardiac troponin <2.3 ng/l), patients in the highest quintile (≥7.7 ng/l) were at greater risk of cardiovascular events (hazard ratio [HR] 3.7; 95% confidence interval [CI]: 1.3 to 10.1; p = 0.012) and cardiovascular death (HR: 20.1; 95% CI: 2.4 to 165.2; p = 0.005) after adjustment for risk factors. By contrast, there were no differences in exacerbations between quintiles (HR: 1.1; 95% CI: 0.8 to 1.5; p = 0.548).Conclusions: In patients with COPD and heightened cardiovascular risk, plasma cardiac troponin I concentrations are a specific and major indicator of future cardiovascular events and cardiovascular death. Inhaled therapies did not affect cardiac troponin I concentrations consistent with their neutral effect on mortality and cardiovascular outcomes. (Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease [SUMMIT]; NCT01313676). [ABSTRACT FROM AUTHOR]