Exercise Ventilatory Inefficiency Adds to Lung Function in Predicting Mortality in COPD

Severity of resting functional impairment only partially predicts the increased risk of death in chronic obstructive pulmonary disease (COPD). Increased ventilation during exercise is associated with markers of disease progression and poor prognosis, including emphysema extension and pulmonary vascular impairment. Whether excess exercise ventilation would add to resting lung function in predicting mortality in COPD, however, is currently unknown. After an incremental cardiopulmonary exercise test, 288 patients (forced expiratory volume in one second ranging from 18% to 148% predicted) were followed for a median (interquartile range) of 57 (47) months. Increases in the lowest (nadir) ventilation to CO₂ output (VCO₂) ratio determined excess exercise ventilation. Seventy-seven patients (26.7%) died during follow-up: 30/77 (38.9%) deaths were due to respiratory causes. Deceased patients were older, leaner, had a greater co-morbidity burden (Charlson Index) and reported more daily life dyspnea. Moreover, they had poorer lung function and exercise tolerance (p < 0.05). A logistic regression analysis revealed that ventilation/VCO₂ nadir was the only exercise variable that added to age, body mass index, Charlson Index and resting inspiratory capacity (IC)/total lung capacity (TLC) ratio to predict all-cause and respiratory mortality (p < 0.001). Kaplan–Meier analyses showed that survival time was particularly reduced when ventilation/VCO₂ nadir > 34 was associated with IC/TLC ≤ 0.34 or IC/TLC ≤ 0.31 for all-cause and respiratory mortality, respectively (p < 0.001). Excess exercise ventilation is an independent prognostic marker across the spectrum of COPD severity. Physiological abnormalities beyond traditional airway dysfunction and lung mechanics are relevant in determining the course of the disease.     

Differences in Adherence to Common Inhaled Medications in COPD

Objective: To study differences in adherence to common inhaled medications in COPD.

Methods: Adherence of 795 patients was recorded from pharmacy records over 3 years in the COMIC cohort. It was expressed as percentage and deemed good at ≥75–≤125%, sub-optimal ≥50–<75%, and poor <50% (underuse) or >125% (overuse). Most patients used more than one medication, so we present 1379 medication periods.

Results: The percentages of patients with good therapy adherence ranged from 43.2 (beclomethasone) –75.8% (tiotropium); suboptimal from 2.3 (budesonide) –23.3% (fluticasone); underuse from 4.4 (formoterol/budesonide) –18.2% (beclomethasone); and overuse from 5.1 (salmeterol) –38.6% (budesonide). Patients using fluticasone or salmeterol/fluticasone have a 2.3 and 2.0-fold increased risk of suboptimal versus good adherence compared to tiotropium. Patients using salmeterol/fluticasone or beclomethasone have a 2.3- and 4.6-fold increased risk of underuse versus good adherence compared to tiotropium. Patients using budesonide, salmeterol/fluticasone, formoterol/budesonide, ciclesonide and beclomethasone have an increased risk of overuse versus good adherence compared to tiotropium. Adherence to inhalation medication is inversely related to lung function.

Conclusion: Therapy adherence to inhalation medication for the treatment of COPD is in our study related to the medication prescribed. Tiotropium showed the highest percentage of patients with good adherence, followed by ciclesonide, both dosed once daily. The idea of improving adherence by using combined preparations cannot be confirmed in this study. Further research is needed to investigate the possibilities of improving adherence by changing inhalation medication.     

Genetic predisposition to accelerated decline of lung function in COPD

Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). The environmental factors are better known than the genetic factors. One of the commonest reasons of accelerated forced expiratory volume in one second (FEV₁) decline in COPD is the continuation of the smoking habit. In addition, COPD patients have frequent acute respiratory infections which can also accelerate the decline of FEV₁. All of the gene variants that have been reported in association with accelerated decline of lung function in COPD represent advancement because the findings generate plausible hypotheses about the possible mechanisms by which gene products could accelerate or avert FEV₁ decline. Unfortunately, the results have not been consistently replicated and, animal models required to functionally assess the genetic findings, have not yet yielded sufficient data. Genome-wide association studies should provide more definitive results in COPD and other multigenic conditions. Until these studies are reported, the data to date suggest that products encoded by the alpha-1 antitrypsin, some matrix metalloproteinases, and a number of antioxidant genes are associated with accelerated FEV₁ decline in COPD. Data on gene variants associated with acute exacerbations of COPD are now emerging.     

Cost-Effectiveness of a Community-Based Exercise Programme in COPD Self-Management

Introduction: Information regarding cost-effectiveness of community-based exercise programmes in COPD is scarce. Therefore, we have investigated whether a community-based exercise programme is a cost-effective component of self-management for patients with COPD after 2 years of follow-up.

Methods: All included COPD patients participated in four self-management sessions. Additionally, patients in the COPE-active group participated in an 11-month community-based exercise programme led by physiotherapists. Patients trained 3 times/week for 6 months and two times/week during the subsequent 5 months. In both periods, one of these weekly training sessions was home-based (unsupervised). No formal physiotherapy sessions were offered to COPE-active patients in the second year. A decision analytical model with a 24-month perspective was used to evaluate cost-effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated and cost-effectiveness planes were created.

Results: Data of 77 patients participating in the exercise programme and 76 patients in the control group were analysed. The ICER for an additional patient prevented from deteriorating at least 47.5 meters on the ISWT was €6257. The ICER for an additional patient with a clinically relevant improvement (≥ 500 steps/day) in physical activity was €1564, and the ICER for an additional quality-adjusted life year (QALY) was €10 950.

Conclusion: Due to a lack of maintenance of beneficial effects on our primary outcome exercise capacity after 2 years of follow-up and higher costs of the programme, the community-based exercise programme cannot be considered cost-effective compared to self-management programmes only. Nevertheless, the ICERs for the secondary outcomes physical activity and QALY are generally considered acceptable.     

Six-minute Stepper Test to Set Pulmonary Rehabilitation Intensity in Patients with COPD – A Retrospective Study

Pulmonary rehabilitation (PR) improves outcomes in patients with chronic obstructive pulmonary disease (COPD). Optimal assessment includes cardiopulmonary exercise testing (CPET), but consultations are limited. Field tests could be used to individualize PR instead of CPET. The six-minute stepper test (6MST) is easy to set up and its sensitivity and reproducibility have previously been reported in patients with COPD. The aim of this study was to develop a prediction equation to set intensity in patients attending PR, based on the 6MST. The following relationships were analyzed: mean heart rate (HR) during the first (HR_1–3) and last (HR_4–6) 3 minutes of the 6MST and HR at the ventilatory threshold (HRvt) from CPET; step count at the end of the 6MST and workload at the Ventilatory threshold (VT) (Wvt); and forced expiratory volume in 1 second and step count during the 6MST. This retrospective study included patients with COPD referred for PR who underwent CPET, pulmonary function evaluations and the 6MST. Twenty-four patients were included. Prediction equations were HRvt = 0.7887 × HR_1–3 + 20.83 and HRvt = 0.6180 × HR_4–6 + 30.77. There was a strong correlation between HR_1–3 and HR_4–6 and HRvt (r = 0.69, p < 0.001 and r = 0.57, p < 0.01 respectively). A significant correlation was also found between step count and LogWvt (r = 0.63, p < 0.01). The prediction equation was LogWvt = 0.001722 × step count + 1.248. The 6MST could be used to individualize aerobic training in patients with COPD. Further prospective studies are needed to confirm these results.     

Endurance Exercise Training Improves Heart Rate Recovery in Patients with COPD

Background: Abnormalities of autonomic function have been reported in patients with chronic obstructive pulmonary disease. The effect of the exercise training in heart rate recovery (HRR) has not been established in patients with COPD. Objective: To assess the effects of 8-weeks’ endurance training program on parasympathetic nervous system response measured as heart rate recovery in a sample of moderate-to-severe COPD patients. Methods: We recruited a consecutive sample of patients with COPD candidates to participate in a pulmonary rehabilitation program from respiratory outpatient clinics of a tertiary hospital. HRR was calculated, before and after training, as the difference in heart rate between end-exercise and one minute thereafter (HRR₁) in a constant-work rate protocol. Results: A total of 73 COPD patients were included: mean (SD) age 66 (8) years, median (P₂₅-P₇₅) post-bronchodilator FEV₁ 39 (29–53)%. The prevalence of slow HRR₁ (≤12 beats) at baseline was 63%, and was associated with spirometric severity (mean FEV₁ 35% in slow HRR₁ vs 53 in normal HRR₁, p < 0.001). After 8-weeks training, HRR₁ improved from mean (SD) 10 (7) to 12 (7) beats (p = 0.0127). Multivariate linear regression models showed that the only variable related to post-training HRR₁ was pre-training HRR₁ (p < 0.001). Conclusions: These results suggest that training enhances HRR in patients with moderate-to-severe COPD. HRR is an easy tool to evaluate ANS such that it may be a useful clinical marker of parasympathetic nervous system response in patients with COPD.     

Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I)

Abstract

Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%–1.6%; constipation: 0%-1.1%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo.

Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as “Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)”.     

The Use of Non-invasive Ventilation during Exercise Training in COPD Patients

Non-invasive ventilation (NIV) is increasingly used in addition to exercise training in patients with chronic obstructive pulmonary disease with the purpose to allow them to train at higher intensities. Different modalities of assisted ventilation have been used with benefits for relief of dyspnoea and increase in exercise capacity. Nevertheless there are some potential problems with the use of NIV in pulmonary rehabilitation programmes. Despite promising results, a generalised use of NIV during exercise training programmes is unlikely to have a role in routine settings. The use of NIV during exercise training as a component of pulmonary rehabilitation should be reserved to individual cases.     

L-精氨酸对COPD患者心肺功能的影响

目的探讨L-精氨酸对COPD患者肺功能及心功能的影响。方法将60例COPD患者随机分为常规组和观察组各30例。常规组给予平喘、吸氧、强心、祛痰、抗感染、利尿、纠正内环境紊乱等治疗;观察组在此基础上使用L-精氨酸进行治疗。比较两组患者治疗前后的肺功能及心功能改变。结果治疗后两组PAP、MIP、MEP、FEV1(%)、FEV1/FVC(%)均较治疗前显著改善(P0.05)。观察组治疗后PAP(mmHg)、MIP(kPa)、MEP(kPa)、FEV1(%)、FEV1/FVC(%)值分别为22.5、7.2、10.6、58.4、66.2,显著高于常规组35.4、6.3、9.2、54.2、63.1(P0.05)。两组治疗后LVEDV、EF、CI均较治疗前有所改善,但差异并无显著性(P0.05)。结论 L-精氨酸与常规治疗相比可以显著改善患者的肺功能并有效降低肺动脉压;其对患者心功能的影响有待于更进一步的研究。     

Impaired Carbon Monoxide Diffusing Capacity is the Strongest Predictor of Exercise Intolerance in COPD

Abstract

Background: Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD) and forced expiratory volume in one second (FEV₁) is the traditional metric used to define the severity of COPD. However, there is dissociation between FEV₁ and exercise capacity in a large proportion of subjects with COPD. The aim of this study was to investigate whether other lung function parameters have an additive, predictive value for exercise capacity and whether this differs according to the COPD stage. Methods: Spirometry, body plethysmography and diffusing capacity for carbon monoxide (DLCO) were performed on 88 patients with COPD GOLD stages II-IV. Exercise capacity (EC) was determined in all subjects by symptom-limited, incremental cycle ergometer testing. Results: Significant relationships were found between EC and the majority of lung function parameters. DLCO, FEV₁ and inspiratory capacity (IC) were found to be the best predictors of EC in a stepwise regression analysis explaining 72% of EC. These lung function parameters explained 76% of EC in GOLD II, 72% in GOLD III and 40% in GOLD IV. DLCO alone was the best predictor of exercise capacity in all GOLD stages. Conclusions: Diffusing capacity was the strongest predictor of exercise capacity in all subjects. In addition to FEV₁, DLCO and IC provided a significantly higher predictive value regarding exercise capacity in COPD patients. This suggests that it is beneficial to add measurements of diffusing capacity and inspiratory capacity when clinically monitoring COPD patients.     

Roflumilast: clinical benefit in patients suffering from COPD

Background and aims: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity and mortality and is characterised by persistent airway inflammation, which leads to impaired airway function, quality of life and intermittent exacerbations. In spite of recent advances in the treatment of COPD, new treatment options for COPD are clearly necessary. The oral phosphodiesterase‐4 (PDE4) inhibitor roflumilast represents a new class of drugs that has shown efficacy and acceptable tolerability in preclinical and short‐term clinical studies in patients with COPD. Methods and results: The available long‐term clinical studies reviewed here suggest that the clinical efficacy of roflumilast is likely because of the suppression of airway inflammation and not through bronchodilation. Furthermore, the clinical studies have shown a modest improvement in airway function, including FEV₁, and a reduction in frequency and severity of COPD exacerbations, as well as a positive effect on several patient‐reported outcomes. The clinical benefit of roflumilast appears to be greatest in patients with more symptomatic and severe disease who experience exacerbations. The most common adverse effects are gastrointestinal events, primarily diarrhoea, nauseas and weight loss. Conclusion: Roflumilast is beneficial for maintenance treatment of patients with severe and symptomatic COPD and with a history of frequent acute exacerbations as an add‐on to treatment with long‐acting bronchodilators. It may have a role as an alternative to inhaled corticosteroids in more symptomatic COPD patients with frequent exacerbations, although direct comparisons are currently lacking. Please cite this paper as: Ulrik CS and Calverley PMA. Roflumilast: clinical benefit in patients suffering from COPD. Clin Respir J 2010; 4: 197–201.     

慢性阻塞性肺病患者肺功能与左心舒张功能变化的关系

目的 研究COPD患者肺功能变化与左心舒张功能变化的关系.方法 对65例COPD（GOLD分级Ⅰ-Ⅳ级）患者,通过肺功能仪测定肺功能FVC（用力肺活量）、FEV1（1s用力呼气量）、FEV1/FVC、FEV1Pred%1s（用力呼气量占预计值的百分比）、RV/TLC（残总比）、Dlco（一氧化碳弥散量）、DLco/VA（单位肺泡容积的一氧化碳弥散量）;通过经胸超声心动图测定LVIDd（左室舒张末内径）、LVIDs（左室收缩末内径）、SPAP（肺动脉压力）、EF（射血分数）、SV（每搏输出量）、左室短轴缩短率（FS）.分析COPD患者的肺功能受损程度与左心舒张功能变化的相关性.结果 四组间LVIDd、LVSV、FS均有显著性差异,而LVIDs、LVEF各组间无显著性差异.LVIDd、LVSV、FS等参数随着COPD分级的增加有下降.COPD患者的FEV1/FVC、RV/TLC、Dlco与LVIDd呈正相关.结论 左心舒张功能与COPD分级程度有关,随着COPD患者气道阻塞程度、肺残气量的增加左心舒张功能有不同程度的减退.     

Role of mucolytics in the management of COPD

There is, to date, no medical therapy that modifies the decline in lung function that occurs in COPD. As the disease becomes more severe, exacerbations of COPD become increasingly common, affecting patient quality of life and increasing health care costs. Mucolytic agents, through their actions on inflammatory and oxidative pathways, have potential benefits in COPD. This paper reviews the randomized controlled trial (RCT) evidence for the effectiveness of at least 2 months of daily therapy with oral mucolytics in COPD. Based on evidence from 26 RCTs, mucolytics reduce exacerbations by up to 0.8 exacerbations per year, with a greater effect in patients with more severe COPD. This effect appears to be of a similar magnitude to the reduction in exacerbations seen with tiotropium and inhaled corticosteroids (ICS), but RCTs that compared the agents would be required to confirm this. Mucolytics do not affect the rate of lung function decline, but they do not have any significant adverse effects. Mucolytic treatment should be considered in: patients with more severe COPD who have frequent or prolonged exacerbations; those who are repeatedly admitted to hospital; or in those patients with frequent exacerbations who are unable to take tiotropium or ICS.     

Outcomes of Pulmonary Rehabilitation for COPD in Older Patients: A Comparative Study

Pulmonary rehabilitation (PR) is established as an effective intervention in optimising function and quality of life in patients with chronic obstructive pulmonary disease (COPD). However, there are very limited data on the effectiveness of PR in older patients with COPD. We reviewed all patients attending an 8-week outpatient programme. Patients were divided into two groups; Group A (n = 202), below 70 years, and Group B (n = 122), above 70 years of age. Outcomes in both patient subgroups were compared using FEV¹, Incremental Shuttle Walk Test (ISWT), Endurance Shuttle Walk Test (ESWT), Grip Strength, St. George's Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Score (HADS), and COPD Assessment Test (CAT) score. Statistical analysis was conducted using Mann-Whitney non-parametric testing and chi-square testing for comparison of clinically relevant improvements between groups. There was no significant difference in PR outcomes between Group A and Group B using absolute values. Mean changes in ISWT for Groups A and B 39.7 m vs. 32.8 m (p = 0.63), respectively, SGRQ ?2.5 vs. ?2.8 (p = 0.95), HADS anxiety score ?0.83 vs. ?0.57 (p = 0.43) and HADS depression score ?0.69 vs. ?0.39 (p = 0.48), respectively. There was no difference in the proportion of patients who achieved the minimal clinically significant improvement in Group A versus Group B for parameters ISWT (38.6% vs 42.7%), SGRQ (27.8% vs 21.3%), and HADS total score (20.5% vs 28.1%). These data suggest that benefits of PR in COPD are not age dependent. Age should not be a barrier to enrolling patients with COPD in PR programmes.     

The role for N-acetylcysteine in the management of COPD

Oxidative stress has been implicated in the pathogenesis and progression of COPD. Both reactive oxidant species from inhaled cigarette smoke and those endogenously formed by inflammatory cells constitute an increased intrapulmonary oxidant burden. Structural changes to essential components of the lung are caused by oxidative stress, contributing to irreversible damage of both parenchyma and airway walls. The antioxidant N-acetylcysteine (NAC), a glutathione precursor, has been applied in these patients to reduce symptoms, exacerbations, and the accelerated lung function decline. This article reviews the available experimental and clinical data on the antioxidative effects of NAC in COPD, with emphasis on the role of exhaled biomarkers.