Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of ...chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone.
We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952).
1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 95% CI 0·7-1·0). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group.
Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk.
GlaxoSmithKline.
Background Recommendations on interpreting tests of bronchodilator responsiveness (BDR) are conflicting. We investigated the dependence of BDR criteria on sex, age, height, ethnicity, and severity of ...respiratory impairment. Methods BDR test data were available from clinical patients in the Netherlands, New Zealand, and the United States (n = 15,278; female subjects, 51.7%) and from surveys in Canada, Norway, and five Latin-American countries (n = 16,250; female subjects, 54.7%). BDR calculated according to FEV1 , FVC, and FEV1 /FVC was expressed as absolute change, a percentage of the baseline level (% baseline), a percentage of the predicted value (% predicted), and z score. Results Change (Δ) in FEV1 and FVC, in milliliters, was unrelated to the baseline value but was biased toward age, height, sex, and level of airways obstruction; ΔFEV1 was significantly lower in African Americans. In 1,106 subjects with low FEV1 (200-1,621 mL) the FEV1 increased by 12% to 44.7% relative to baseline but < 200 mL. Expressing BDR as a percentage of the predicted value or as a z score attenuated the bias and made the 200-mL criterion redundant, but reduced positive responses by half. ΔFEV1 % baseline increased with the level of airflow obstruction but decreased with severe obstruction when expressed as z scores or % predicted; ΔFVC, however expressed, increased with the level of airflow obstruction. Conclusions Expressing FEV1 responsiveness as % baseline spuriously suggests that responsiveness increases with the severity of respiratory impairment. Expressing change in FEV1 or FVC as % predicted or as z scores eliminates this artifact and renders the required 200-mL minimum increase redundant. In severe airways obstruction ΔFVC should be critically evaluated as an index of clinically important relief of hyperinflation, with implications for bronchodilator drug trials.
Abstract Purpose The way in which spirometry is interpreted can lead to misdiagnosis of chronic obstructive pulmonary disease (COPD) resulting in inappropriate treatment. We compared the clinical ...relevance of 2 criteria for defining a low ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1 /FVC): the fixed ratio and the lower limit of normal. Methods We analyzed data from the cross-sectional phase of the population-based Canadian Cohort of Obstructive Lung Disease (CanCOLD) study. We determined associations of the spirometric criteria for airflow limitation with patient-reported adverse outcomes, including respiratory symptoms, disability, health status, exacerbations, and cardiovascular disease. Sensitivity analyses were used to explore the impact of age and severity of airflow limitation on these associations. Results We analyzed data from 4,882 patients aged 40 years and older. The prevalence of airflow limitation was 17% by fixed ratio and 11% by lower limit of normal. Patients classified as having airflow limitation by fixed ratio only had generally small, nonsignificant increases in the odds of adverse outcomes. Patients having airflow limitation based on both fixed ratio and lower limit of normal had larger, significant increases in odds. But strongest associations were seen for patients who had airflow limitation by both fixed ratio and lower limit of normal and also had a low FEV1 , defined as one less than 80% of the predicted value. Conclusions Our results suggest that use of the fixed ratio alone may lead to misdiagnosis of COPD. A diagnosis established by both a low FEV1 /FVC (according to fixed ratio and/or lower limit of normal) and a low FEV1 is strongly associated with clinical outcomes. Guidelines should be reconsidered to require both spirometry abnormalities so as to reduce overdiagnosis of COPD.
Study objective The variable effectiveness of clinical asthma pathways to reduce hospital admissions may be explained in part by the timing of systemic corticosteroid administration. We examine the ...effect of early (within 60 minutes SD 15 minutes of triage) versus delayed (>75 minutes) administration of systemic corticosteroids on health outcomes. Methods We conducted a prospective observational cohort of children aged 2 to 17 years presenting to the emergency department with moderate or severe asthma, defined as a Pediatric Respiratory Assessment Measure (PRAM) score of 5 to 12. The outcomes were hospital admission, relapse, and length of active treatment; they were analyzed with multivariate logistic and linear regressions adjusted for covariates and potential confounders. Results Among the 406 eligible children, 88% had moderate asthma; 22%, severe asthma. The median age was 4 years (interquartile range 3 to 8 years); 64% were male patients. Fifty percent of patients received systemic corticosteroids early; in 33%, it was delayed; 17% of children failed to receive any. Overall, 36% of patients were admitted to the hospital. Compared with delayed administration, early administration reduced the odds of admission by 0.4 (95% confidence interval 0.2 to 0.7) and the length of active treatment by 0.7 hours (95% confidence interval −1.3 to −0.8 hours), with no significant effect on relapse. Delayed administration was positively associated with triage priority and negatively with PRAM score. Conclusion In this study of children with moderate or severe asthma, administration of systemic corticosteroids within 75 minutes of triage decreased hospital admission rate and length of active treatment, suggesting that early administration of systemic corticosteroids may allow for optimal effectiveness.
The burden of chronic obstructive pulmonary disease (COPD) in the USA continues to grow. Although progress has been made in the the development of diagnostics, therapeutics, and care guidelines, ...whether patients' quality of life is improved will ultimately depend on the actual implementation of care and an individual patient's access to that care. In this Commission, we summarise expert opinion from key stakeholders-patients, caregivers, and medical professionals, as well as representatives from health systems, insurance companies, and industry-to understand barriers to care delivery and propose potential solutions. Health care in the USA is delivered through a patchwork of provider networks, with a wide variation in access to care depending on a patient's insurance, geographical location, and socioeconomic status. Furthermore, Medicare's complicated coverage and reimbursement structure pose unique challenges for patients with chronic respiratory disease who might need access to several types of services. Throughout this Commission, recurring themes include poor guideline implementation among health-care providers and poor patient access to key treatments such as affordable maintenance drugs and pulmonary rehabilitation. Although much attention has recently been focused on the reduction of hospital readmissions for COPD exacerbations, health systems in the USA struggle to meet these goals, and methods to reduce readmissions have not been proven. There are no easy solutions, but engaging patients and innovative thinkers in the development of solutions is crucial. Financial incentives might be important in raising engagement of providers and health systems. Lowering co-pays for maintenance drugs could result in improved adherence and, ultimately, decreased overall health-care spending. Given the substantial geographical diversity, health systems will need to find their own solutions to improve care coordination and integration, until better data for interventions that are universally effective become available.
Background ADAM33 , a disintegrin and metalloproteinase 33 gene, has been identified as a risk factor for asthma and bronchial hyperresponsiveness and has been postulated as a gene for airway ...remodeling. ADAM8 is strongly induced by allergens and TH 2 cytokines in the lung in experimental asthma. Objectives To assess the importance of these genes in asthma pathogenesis and to investigate whether expression relates to disease severity or deterioration in lung function, we measured the mRNA and protein expression of both genes in bronchial biopsies of subjects with asthma and control subjects. Methods RNA was extracted from frozen endobronchial biopsies of mild, moderate, and severe adults with asthma and controls. Subjects with moderate and severe asthma were taking corticosteroids. The mRNA transcript of both genes was measured by real time RT-PCR using specific primers. Protein expression was examined by immunohistochemistry on paraffin sections. Results ADAM33 mRNA expression was significantly higher in both moderate and severe asthma compared with mild asthma ( P < .05) and controls. Immunostaining for ADAM33 was increased in the epithelium, submucosal cells, and smooth muscle in severe asthma compared with mild disease and controls. ADAM8 mRNA expression was significantly increased in all asthma groups compared with controls. Increased inflammatory cells stained positive for ADAM8 in both moderate ( P < .05) and severe asthma ( P < .005) compared with mild disease. Conclusions These results demonstrate increased expression of both ADAM genes as asthma severity increases. Clinical implications These genes may contribute to the remodeling process that occurs with asthma progression and may have implications for future treatment in severe disease.
Prevention of Acute Exacerbations of COPD Criner, Gerard J., MD, FCCP; Bourbeau, Jean, MD, FCCP; Diekemper, Rebecca L., MPH ...
Chest,
April 2015, Letnik:
147, Številka:
4
Journal Article
Recenzirano
BACKGROUND:COPD is a major cause of morbidity and mortality in the United States as well as throughout the rest of the world. An exacerbation of COPD (periodic escalations of symptoms of cough, ...dyspnea, and sputum production) is a major contributor to worsening lung function, impairment in quality of life, need for urgent care or hospitalization, and cost of care in COPD. Research conducted over the past decade has contributed much to our current understanding of the pathogenesis and treatment of COPD. Additionally, an evolving literature has accumulated about the prevention of acute exacerbations. METHODS:In recognition of the importance of preventing exacerbations in patients with COPD, the American College of Chest Physicians (CHEST) and Canadian Thoracic Society (CTS) joint evidence-based guideline (AECOPD Guideline) was developed to provide a practical, clinically useful document to describe the current state of knowledge regarding the prevention of acute exacerbations according to major categories of prevention therapies. Three key clinical questions developed using the PICO (population, intervention, comparator, and outcome) format addressed the prevention of acute exacerbations of COPD: nonpharmacologic therapies, inhaled therapies, and oral therapies. We used recognized document evaluation tools to assess and choose the most appropriate studies and to extract meaningful data and grade the level of evidence to support the recommendations in each PICO question in a balanced and unbiased fashion. RESULTS:The AECOPD Guideline is unique not only for its topic, the prevention of acute exacerbations of COPD, but also for the first-in-kind partnership between two of the largest thoracic societies in North America. The CHEST Guidelines Oversight Committee in partnership with the CTS COPD Clinical Assembly launched this project with the objective that a systematic review and critical evaluation of the published literature by clinical experts and researchers in the field of COPD would lead to a series of recommendations to assist clinicians in their management of the patient with COPD. CONCLUSIONS:This guideline is unique because it provides an up-to-date, rigorous, evidence-based analysis of current randomized controlled trial data regarding the prevention of COPD exacerbations.
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