Roger S. Goldstein

Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease

BACKGROUND Respiratory rehabilitation is increasingly recognised as an important part of the management of patients with chronic obstructive pulmonary disease (COPD). The widespread application of such programmes should be preceded by evidence of directly attributable improvements in function. We assessed the effect of respiratory rehabilitation on exercise capacity and health-related quality of life (HRQL) in patients with COPD. METHODS We carried out a meta-analysis of randomised controlled trials of respiratory rehabilitation in patients with COPD that assessed functional or maximal exercise capacity, HRQL, or both. Respiratory rehabilitation was defined as exercise training (for at least 4 weeks) with or without education, psychological support, or both. The most commonly used measure for HRQL was the chronic respiratory questionnaire, in which responses were presented on a 7-point scale. The control groups received no rehabilitation. Within each trial and for each outcome an effect size was calculated; the effect sizes were then pooled by a random-effects model. The overall effect of treatment was compared with its minimum clinically important difference (MCID)--defined as the smallest difference perceived as important by the average patient. FINDINGS We included 14 trials. Significant improvements were found for all the outcomes. For two important features of HRQL, dyspnoea and mastery, the overall treatment effect was larger than the MCID: 1.0 (95% CI 0.6-1.5) and 0.8 (0.5-1.2), respectively, compared with an MCID of 0.5. For functional exercise capacity (6-min walk test), the overall effect was 55.7 m (27.8-92.8), and for maximum exercise capacity (incremental cycle ergometer test), 8.3 W (2.8-16.5). Functional exercise capacity showed heterogeneity that could not be explained by the sensitivity analyses. INTERPRETATION Respiratory rehabilitation relieves dyspnoea and improves the control over COPD. These improvements are clinically important. The value of the improvement in exercise capacity is not clear. Respiratory rehabilitation is an effective part of care in patients with COPD.

Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease - 2007 update

Chronic obstructive pulmonary disease (COPD) is a major respiratory illness in Canada that is both preventable and treatable. Our understanding of the pathophysiology of this complex condition continues to grow and our ability to offer effective treatment to those who suffer from it has improved considerably. The purpose of the present educational initiative of the Canadian Thoracic Society (CTS) is to provide up to date information on new developments in the field so that patients with this condition will receive optimal care that is firmly based on scientific evidence. Since the previous CTS management recommendations were published in 2003, a wealth of new scientific information has become available. The implications of this new knowledge with respect to optimal clinical care have been carefully considered by the CTS Panel and the conclusions are presented in the current document. Highlights of this update include new epidemiological information on mortality and prevalence of COPD, which charts its emergence as a major health problem for women; a new section on common comorbidities in COPD; an increased emphasis on the meaningful benefits of combined pharmacological and nonpharmacological therapies; and a new discussion on the prevention of acute exacerbations. A revised stratification system for severity of airway obstruction is proposed, together with other suggestions on how best to clinically evaluate individual patients with this complex disease. The results of the largest randomized clinical trial ever undertaken in COPD have recently been published, enabling the Panel to make evidence-based recommendations on the role of modern pharmacotherapy. The Panel hopes that these new practice guidelines, which reflect a rigorous analysis of the recent literature, will assist caregivers in the diagnosis and management of this common condition.

Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone–Salmeterol for Treatment of Chronic Obstructive Pulmonary Disease: A Randomized Trial

Context Physicians use multiple medications to treat chronic obstructive pulmonary disease (COPD). Contribution In this multicenter trial, 449 adults with moderate or severe COPD were randomly assigned to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and fluticasonesalmeterol for 1 year. About 63%, 65%, and 60% of patients, respectively, had exacerbations. The third group, but not the second group, had better lung function and fewer hospitalizations than the first group. Caution Many patients discontinued assigned medications. Implications Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations, but it does not affect reduce exacerbations in patients with moderate or severe COPD. The Editors Most patients with moderate or severe chronic obstructive pulmonary disease (COPD) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators. It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms (1). Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms, improve health status, and reduce the frequency of COPD exacerbations (2, 3), and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals (2, 3). In the past several years, several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium (47); the long-acting 2-agonist salmeterol (810); or products that combine inhaled steroids and long-acting 2-agonists, such as fluticasonesalmeterol or budesonideformoterol (1114), improve dyspnea and quality of life and decrease exacerbation rates compared with placebo. However, no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone. 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation (15), and inhaled corticosteroids may have an anti-inflammatory effect in COPD (16). Thus, it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone. However, safety concerns, such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids, and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy. We therefore conducted a randomized, double-blind, placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone. Methods Design We designed a parallel-group, 3-group, randomized, double-blind, placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006. The study protocol has been published elsewhere (17). The research ethics boards of all participating centers approved the study, and all trial participants provided written informed consent. Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers. Twenty centers were academic hospitalbased pulmonary clinics, 5 were community-based pulmonary clinics, and 2 were community-based primary care clinics. Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before randomization. Additional inclusion criteria were age older than 35 years; a history of 10 pack-years or more of cigarette smoking; and documented chronic airflow obstruction, with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value. We excluded patients with a history of physician-diagnosed asthma before 40 years of age; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction; those receiving oral prednisone; those with a known hypersensitivity or intolerance to tiotropium, salmeterol, or fluticasonesalmeterol; those with a history of severe glaucoma or severe urinary tract obstruction, previous lung transplantation or lung volume reduction surgery, or diffuse bilateral bronchiectasis; and those who were pregnant or were breastfeeding. Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study. Randomization and Interventions We randomly assigned patients to 1 of 3 treatment groups for 52 weeks: tiotropium (Spiriva [Boehringer Ingelheim Pharma, Ingelheim, Germany]), 18 g once daily, plus placebo inhaler, 2 puffs twice daily; tiotropium, 18 g once daily, plus salmeterol (Serevent [GlaxoSmithKline, Research Triangle Park, North Carolina]), 25 g/puff, 2 puffs twice daily; or tiotropium, 18 g once daily, plus fluticasonesalmeterol (Advair [GlaxoSmithKline]), 250/25 g/puff, 2 puffs twice daily. Randomization was done through central allocation of a randomization schedule that was prepared from a computer-generated random listing of the 3 treatment allocations, blocked in variable blocks of 9 or 12 and stratified by site. Neither research staff nor patients were aware of the treatment assignment before or after randomization. All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms. Any treatment with inhaled corticosteroids, long-acting 2-agonists, and anticholinergics that the patient may have been using before entry was discontinued on entry into the study. Therapy with other respiratory medications, such as oxygen, antileukotrienes, and methylxanthines, was continued in all patient groups. Tiotropium was administered by using a Handihaler device (Boehringer Ingelheim). Study drugs were administered through a pressurized metered-dose inhaler using a spacer device (Aerochamber Plus, Trudell Medical, London, Ontario, Canada), and patients were taught the correct inhalation technique to ensure adequate drug delivery. The metered-dose inhalers containing placebo, salmeterol, and fluticasonesalmeterol were identical in taste and appearance, and they were enclosed in identical tamper-proof blinding devices. The medication canisters within the blinding devices were stripped of any identifying labeling. Adherence to therapy was assessed by weighing the returned inhaler canisters. Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of randomization. Respiratory exacerbations were defined, according to the 2000 Aspen Lung Conference Consensus definition, as a sustained worsening of the patients respiratory condition, from the stable state and beyond normal day-to-day variations, necessitating a change in regular medication in a patient with underlying COPD (18). An acute change in regular COPD medications was defined as physician-directed, short-term use of oral or intravenous steroids, oral or intravenous antibiotics, or both therapies. Secondary outcomes were the mean number of COPD exacerbations per patient-year; the total number of exacerbations that resulted in urgent visits to a health care provider or emergency department; the number of hospitalizations for COPD; the total number of hospitalizations for all causes; and changes in health-related quality of life, dyspnea, and lung function. Health-related quality of life was assessed by using the St. Georges Respiratory Questionnaire (19), dyspnea was assessed by using the Transitional Dyspnea Index (20) and the dyspnea domain of the Chronic Respiratory Disease Questionnaire (21), and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society. Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls. Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4, 20, 36, and 52 weeks after randomization. For every suspected exacerbation, we contacted both the patient and the patients treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report, including physician, emergency department, and hospital records that described the circumstances of each suspected exacerbation, was prepared. The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review, and the committee confirmed whether the encounter met the study definition of COPD exacerbation. For the purposes of the trial, we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation. Patients were followed for the full 52-week duration of the trial, and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications. We did not break the study blinding for patients who prematurely discontinued treatment with study medications. Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects. Physicians rated events as expected or unexpected, and they were asked to rate event severity and attribute causality of adverse events to the study drugs. Statistical Analysis We designed the study to detect an 18% absolute d

Randomised controlled trial of respiratory rehabilitation

Disability associated with chronic obstructive pulmonary disease has led to the development of rehabilitation programmes that aim to increase exercise tolerance and improve quality of life. Many reports of the benefits of rehabilitation have been from uncontrolled trials and unsupervised programmes. In view of the commitment asked of patients, their families, and health-care professionals, rehabilitation should be justified by a demonstration of sustained improvement over conventional treatment. We undertook a prospective randomised controlled trial of respiratory rehabilitation in 89 subjects (44 men, 45 women) aged 66 (SD 7) years with severe but stable chronic obstructive pulmonary disease who received rehabilitation or conventional community care. The treatment group were rehabilitated as inpatients for 8 weeks and supervised as outpatients for 16 weeks. Primary outcome measures of exercise tolerance and quality of life were made at baseline and repeated at 12, 18, and 24 weeks. The difference between baseline and last follow-up was significant for 6 min walk distance (37.9 m [95% CI 10.8-65.0], p = 0.0067) and submaximal cycle time (4.7 min [2.1-7.3]). There were also significant differences in questionnaire assessment of dyspnoea (p = 0.0061), emotional function (p = 0.0150), mastery (p = 0.0002), and dyspnoea index (p = 0.0053). Improvements in exercise tolerance and quality of life can be achieved and sustained for 6 months in patients undergoing respiratory rehabilitation compared with those receiving conventional care.

Interpreting treatment effects in randomised trials

The need to measure the impact of treatments on health related quality of life has led to a rapid increase in the variety of instruments available and in their use as measures of outcome in clinical trials. One limitation of instruments that purport to measure health related quality of life is difficulty interpreting their results. In the past decade, investigators have progressed in making these questionnaire results interpretable. For example, we have shown that when questionnaires present response options in the form of seven point scales with verbal descriptions for each option (see box), the smallest difference that patients consider important is often approximately 0.5 per question. A moderate difference corresponds to a change of approximately 1.0 per question, and changes of greater than 1.5 can be considered large. Thus, for example, in a domain with four items, patients will consider a 1 point change in two or more items as important. This finding applies across different areas of function, including dyspnoea, fatigue, and emotional function in patients with chronic airflow limitation1; and symptoms, emotional function, and activity limitations in adults2 and children3 with asthma, parents of children with asthma,4 and adults with rhinoconjunctivitis.5 Initially, we used comparisons in the same patient to establish this difference, but more recently we have replicated this finding using differences between patients.6 #### Summary points Several questionnaires on quality of life related to health are available, but interpreting their results may be difficult For some questionnaires, we now know that the smallest change in score that patients consider important is 0.5 Even if the mean difference between a treatment and a control is appreciably less than the smallest change that is important, treatment may have an important impact on many patients A method for estimating the proportion of patients who …

Anxiety and Depression in COPD: Current Understanding, Unanswered Questions, and Research Needs

BACKGROUND Approximately 60 million people in the United States live with one of four chronic conditions: heart disease, diabetes, chronic respiratory disease, and major depression. Anxiety and depression are very common comorbidities in COPD and have significant impact on patients, their families, society, and the course of the disease. METHODS We report the proceedings of a multidisciplinary workshop on anxiety and depression in COPD that aimed to shed light on the current understanding of these comorbidities, and outline unanswered questions and areas of future research needs. RESULTS Estimates of prevalence of anxiety and depression in COPD vary widely but are generally higher than those reported in some other advanced chronic diseases. Untreated and undetected anxiety and depressive symptoms may increase physical disability, morbidity, and health-care utilization. Several patient, physician, and system barriers contribute to the underdiagnosis of these disorders in patients with COPD. While few published studies demonstrate that these disorders associated with COPD respond well to appropriate pharmacologic and nonpharmacologic therapy, only a small proportion of COPD patients with these disorders receive effective treatment. CONCLUSION Future research is needed to address the impact, early detection, and management of anxiety and depression in COPD.BACKGROUND Approximately 60 million people in the United States live with one of four chronic conditions: heart disease, diabetes, chronic respiratory disease, and major depression. Anxiety and depression are very common comorbidities in COPD and have significant impact on patients, their families, society, and the course of the disease. METHODS We report the proceedings of a multidisciplinary workshop on anxiety and depression in COPD that aimed to shed light on the current understanding of these comorbidities, and outline unanswered questions and areas of future research needs. RESULTS Estimates of prevalence of anxiety and depression in COPD vary widely but are generally higher than those reported in some other advanced chronic diseases. Untreated and undetected anxiety and depressive symptoms may increase physical disability, morbidity, and health-care utilization. Several patient, physician, and system barriers contribute to the underdiagnosis of these disorders in patients with COPD. While few published studies demonstrate that these disorders associated with COPD respond well to appropriate pharmacologic and nonpharmacologic therapy, only a small proportion of COPD patients with these disorders receive effective treatment. CONCLUSION Future research is needed to address the impact, early detection, and management of anxiety and depression in COPD.

Assessing the Minimal Important Difference in Symptoms: A Comparison of Two Techniques

We have developed a method for estimating the minimally important difference (MID) for health status measures. Whereas the conventional approach requires patients to judge themselves relative to their memories, our method requires patients to judge themselves relative to others with the same condition. In this study we examined whether our method (based on between-patient differences) and the conventional method (based on within-patient changes) provides comparable estimates of the MID for one health status measure: the Chronic Respiratory Questionnaire. Patients with chronic obstructive pulmonary disease who were participating in a supervised respiratory rehabilitation program were included if they were in stable health (n = 112). Their mean score per question in the Chronic Respiratory Questionnaire was 4.5 (range, 1 to 7; where bigger values indicate better health). Our method estimated that the MID was 0.5 (95% confidence interval 0.4 to 0.7). This estimate was similar to the MID previously found using the conventional method. These observations support the role of the Chronic Respiratory Questionnaire for measuring patients symptoms, the validity of our approach for assessing the MID, and an estimate on the order of 0.5 as the threshold for this particular health status measure.

Interpretation of treatment changes in 6-minute walk distance in patients with COPD

There is uncertainty about the interpretation of changes in the 6-min walk distance (6MWD) in chronic obstructive pulmonary disease (COPD) patients and whether the minimal important difference (MID) for this useful outcome measure exists. Data were used from nine trials enrolling a wide spectrum of COPD patients with 6MWD at baseline and follow-up and used to determine threshold values for important changes in 6MWD using three distribution-based methods. Anchor-based methods to determine a MID were also evaluated. Data were included of 460 COPD patients with a mean±sd forced expiratory volume in one second (FEV1) of 39.2±14.1% predicted and 6MWD of 361±112 m at baseline. Threshold values for important effects in 6MWD were between 29 and 42 m, respectively, using the empirical rule effect size and the standardised response mean. The threshold value was 35 m (95% confidence interval 30–42 m) based on the standard error of measurement. Correlations of 6MWD with patient-reported anchors were too low to provide meaningful MID estimates. 6-min walk distance should change by ∼35 m for patients with moderate to severe chronic obstructive pulmonary disease in order to represent an important effect. This corresponds to a 10% change of baseline 6-min walk distance. The low correlations of 6-min walk distance with patient-reported anchors question whether a minimal important difference exists for the 6-min walk distance.

The effect of postrehabilitation programmes among individuals with chronic obstructive pulmonary disease

The purpose of this study was to examine the effects of two postrehabilitation programmes on functional exercise tolerance and health-related quality of life in patients with chronic obstructive pulmonary disease (COPD). Subjects with COPD (n=109) were randomised to receive either enhanced follow-up (EF) or conventional follow-up (CF). Subjects in the EF group attended a monthly support group and received a telephone call from a staff member at the midpoint (2 weeks) between their visits. Both groups had scheduled appointments with a physical therapist and physician at 3‐monthly intervals after discharge. Longitudinal data were recorded in 85 subjects (37 EF and 48 CF). Over the course of the study, there was no difference in distance walked in 6 min between the two groups but a significant difference for time and a group-time interaction. There was no difference in total chronic respiratory disease questionnaire score between groups at baseline or at any time interval despite a significant difference with time. There was a clear deterioration in functional exercise capacity and health-related quality of life after completion of respiratory rehabilitation but no difference between the groups.

Generic and Specific Measurement of Health-Related Quality of Life in a Clinical Trial of Respiratory Rehabilitation

The purpose of this study was to compare the performance of measures of health-related quality of life in a randomized controlled trial of respiratory rehabilitation versus conventional community care for patients with chronic airflow limitation. The study included 89 stable patients with moderate to severe chronic airflow limitation with measurement of health status at 12, 18, and 24 weeks. Outcomes included two disease-specific (the Oxygen Cost Diagram and the Chronic Respiratory Questionnaire [CRQ]) measures, a generic health profile (the Sickness Impact Profile [SIP]), and two utility measures (the Standard Gamble and the Quality of Well-Being index [QWB]). Of the measures, only the four domains of the CRQ (dyspnea, fatigue, mastery, and emotional function) showed statistically significant differences (P < or = 0.05) between treatment and control groups. Correlation between change in the CRQ and change in other relevant measures, including the 6-minute walk test and global ratings of change in dyspnea, fatigue, and emotional function were generally weak to moderate (from 0.19 to 0.51). All correlations between change in the QWB, SIP, and Standard Gamble and other measures were very weak or weak (up to 0.30). Correlation between change in the three generic measures were all very weak (<0.15). The results suggest that unless investigators include responsive and valid disease-specific measures of health-related quality of life in controlled trials in chronic diseases, they risk misleading conclusions about the effect of treatments on health status.