Defining a COPD composite safety endpoint for demonstrating efficacy in clinical trials: results from the randomized, placebo-controlled UPLIFT® trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) clinical trials evaluating hard endpoints (mortality, hospitalized exacerbations) require a large number of subjects and prolonged observational periods. We hypothesized that a composite endpoint of respiratory outcomes (CERO) can help evaluate safety and benefit in COPD trials. METHODS: Retrospective analysis of 5992 patients enrolled in the 4-year UPLIFT® trial, a randomized trial of tiotropium versus placebo in patients with moderate-to-severe COPD. Patients were permitted to continue using their usual COPD medications except for other anticholinergics. The CERO included deaths, respiratory failure, hospitalized exacerbations, and trial dropout due to COPD worsening. The incidence rates (IRs) per 100 patient-years and risk ratios (RRs and 95 % CI) were determined at years 1 to 4. The effect of treatments on CERO was similarly assessed. A power analysis helped calculate the sample size needed to achieve outcome differences between treatments. RESULTS: The CERO IRs at years 1 to 4 for tiotropium versus placebo were 16, 13, 11, and 11, and 21, 16, 14, and 13, respectively. The RRs of CERO between tiotropium and placebo at the same time points were: RR-year 0.76 (0.67, 0.86), 0.80 (0.72, 0.88), 0.81 (0.74, 0.89), and 0.84 (0.77, 0.92). Using the IRs and RRs, the sample size (alpha = 0.05 two-sided, 90 % power) for studies of 1, 2, 3, and 4 years would be 1546, 1392, 1216, and 1504 per treatment group, respectively, with 575, 810, 930, 1383 required events, respectively, for hypothetical, event-driven studies. CONCLUSIONS: A composite endpoint incorporating relatively infrequent serious or significant COPD-related safety outcomes could be useful in clinical trials. In UPLIFT®, CERO events were significantly reduced in patients receiving tiotropium compared with placebo. TRIAL REGISTRATION: NCT00144339 .

The Assessment of Burden of COPD (ABC) Scale: A Reliable and Valid Questionnaire.

The newly developed Assessment of Burden of COPD (ABC) scale is a 14-item self-administered questionnaire which measures the physical, psychological, emotional and/or social burden as experienced by patients with chronic obstructive pulmonary disease (COPD). The ABC scale is part of the ABC tool that visualises the outcomes of the questionnaire. The aim of this study was to assess the reliability and construct validity of the ABC scale. This multi-centre survey study was conducted in the practices of 19 general practitioners and 9 pulmonologists throughout the Netherlands. Next to the ABC scale, patients with COPD completed the Saint George Respiratory Questionnaire (SGRQ). Reliability analyses were performed with data from 162 cases. Cronbach's alpha was 0.91 for the total scale. Test-retest reliability, measured at a two week interval (n = 137), had an intra-class correlation coefficient of 0.92. Analyses for convergent validity were performed with data from 133 cases. Discriminant and known-groups validity was analysed with data from 162 cases. The ABC scale total score had a strong correlation with the total score of the SGRQ (r = 0.72, p < 0.001) but a weak correlation with the forced expired volume in 1 second predicted (r = -0.28, p < 0.001). Subgroups with more severe disease, defined by GOLD-stage, frequency of exacerbations, activity level and depression scored statistically significantly (p < 0.05) worse on almost all domains of the ABC scale than the less severe subgroups. The ABC scale seems a valid and reliable tool with good discriminative properties.

Efficacy of a physical exercise training programme COPD in primary care: study protocol of a randomized controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is recognized as a systemic illness with significant extra-pulmonary features, such as exercise intolerance and muscle weakness. Pulmonary rehabilitation has been shown to be very effective in counteracting these consequences in patients with more advanced COPD. However, limited data is available on the efficacy of a physical exercise training programme in patients with mild to moderate COPD in primary care. Furthermore, it is unknown if improved exercise capacity translates into enhanced daily physical activities. The aim of this paper is to describe the design of a randomized controlled trial to assess the efficacy of a physical exercise training programme in patients with mild to moderate COPD. METHODS/DESIGN: In this randomized controlled trial situated in the primary care setting, 102 patients with mild to moderate airflow obstruction (FEV1 ≥ 50% of predicted), dyspnoea and a physically inactive lifestyle will be randomized to an intervention or control group. The intervention group receives a 4-month physical exercise training programme at a local physiotherapy practice, which includes exercise training, resistance training, breathing exercises and advises on how to increase the level of physical activity. The control group receives usual care, i.e. advises on how to increase the level of physical activity and a sham treatment at a local physiotherapy practice of which no physiological training stimulus can be expected. Primary outcome is functional exercise capacity at 4-months measured on the six-minute walk distance. Secondary outcomes include peripheral muscle strength, physical activity in daily life, health related quality of life, Medical Research Council (MRC) dyspnoea score and patients' perceived effectiveness. Follow-up measurement will take place at 6 months after baseline. DISCUSSION: This will be one of the first studies to evaluate the efficacy of a physical exercise training programme in patients with mild to moderate COPD completely recruited and assessed in primary care. The results of this trial may give a unique insight into the potential of the implementation of an easy, close-to-home rehabilitation programme. TRIAL REGISTRATION: The Netherlands National Trial Register NTR1471.

Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial.

BACKGROUND: Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease (COPD). COPD exacerbations in particular negatively impact COPD progression. Physical therapy intervention seems indicated to influence exacerbations and their consequences. However, information on the effect of physical therapy on exacerbation occurrence is scarce. This study aims to investigate the potential of a protocol-directed physical therapy programme as a means to prevent or postpone exacerbations, to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation. Besides, this study focuses on the effect of protocol-directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation. METHODS/DESIGN: A prospective cohort of 300 COPD patients in all GOLD stages will be constructed. Patients will receive usual multidisciplinary COPD care including guideline-directed physical therapy. Patients in this cohort who have GOLD stage 2 to 4 (post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% of predicted), who receive reimbursement by health insurance companies for physical therapy (post-bronchodilator Tiffeneau-index < 0.6) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospective randomised controlled trial (RCT). In this RCT, the intervention group will receive a strict physical therapy programme for patients with COPD. This protocol-directed physical therapy (pdPT) will be compared to a control group that will receive sham-treatment, meaning no or very low-intensity exercise training (ST). An economic evaluation will be embedded in the RCT. Anthropometric measurements, comorbidities, smoking, functional exercise capacity, peripheral muscle strength, physical activity level, health related quality of life, patients' perceived benefit, physical therapy compliance, motivation level, level of effective mucus clearance, exacerbation symptoms and health care contacts due to COPD will be recorded. Follow-up measurements are scheduled at 3 and 6 weeks, 3, 6, 12 and 24 months after inclusion. DISCUSSION: Ways to minimise potential problems regarding the execution of this study will be discussed. TRIAL REGISTRATION: The Netherlands National Trial Register NTR1972.

Effectiveness of the Assessment of Burden of Chronic Obstructive Pulmonary Disease (ABC) tool: study protocol of a cluster randomised trial in primary and secondary care.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a growing worldwide problem that imposes a great burden on the daily life of patients. Since there is no cure, the goal of treating COPD is to maintain or improve quality of life. We have developed a new tool, the Assessment of Burden of COPD (ABC) tool, to assess and visualize the integrated health status of patients with COPD, and to provide patients and healthcare providers with a treatment algorithm. This tool may be used during consultations to monitor the burden of COPD and to adjust treatment if necessary. The aim of the current study is to analyse the effectiveness of the ABC tool compared with usual care on health related quality of life among COPD patients over a period of 18 months. METHODS/DESIGN: A cluster randomised controlled trial will be conducted in COPD patients in both primary and secondary care throughout the Netherlands. An intervention group, receiving care based on the ABC tool, will be compared with a control group receiving usual care. The primary outcome will be the change in score on a disease-specific-quality-of-life questionnaire, the Saint George Respiratory Questionnaire. Secondary outcomes will be a different questionnaire (the COPD Assessment Test), lung function and number of exacerbations. During the 18 months follow-up, seven measurements will be conducted, including a baseline and final measurement. Patients will receive questionnaires to be completed at home. Additional data, such as number of exacerbations, will be recorded by the patients' healthcare providers. A total of 360 patients will be recruited by 40 general practitioners and 20 pulmonologists. Additionally, a process evaluation will be performed among patients and healthcare providers. DISCUSSION: The new ABC tool complies with the 2014 Global Initiative for Chronic Obstructive Lung Disease guidelines, which describe the necessity to classify patients on both their airway obstruction and a comprehensive symptom assessment. It has been developed to classify patients, but also to provide visual insight into the burden of COPD and to provide treatment advice. TRIAL REGISTRATION: Netherlands Trial Register, NTR3788.

How do dyspnoea scales compare with measurement of functional capacity in patients with COPD and at risk of COPD?

BACKGROUND: In primary care, formal functional capacity testing is not always feasible. Guidelines for family practitioners suggest the use of dyspnoea scales to assess exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). AIMS: To examine whether the use of activity-based dyspnoea scales can substitute for actual functional capacity testing. METHODS: 128 subjects (49% at risk of COPD, 24% GOLD stage I, 17% GOLD stage II, 9% GOLD stage III) performed an Incremental Shuttle Walk Test (ISWT) and completed the Medical Research Council dyspnoea scale (MRC), Baseline Dyspnoea Index (BDI), Oxygen Cost Diagram (OCD), Clinical COPD Questionnaire (CCQ), and St George's Respiratory Questionnaire (SGRQ). RESULTS: Analysis of variance showed that the relationship between the ISWT and the MRC dyspnoea scale was statistically significant but moderate (p < 0.001, R2 = 0.166). Correlations between the ISWT and the other dyspnoea scales were also moderate (correlation coefficients 0.34-0.42). Combining the dyspnoea scales in one analysis resulted in a proportion of explained variance of the ISWT of 21.4% (R2 = 0.214). CONCLUSIONS: Dyspnoea scales cannot substitute for formal functional capacity testing. Authors of COPD guidelines should consider stating more specifically that the MRC and similar scales measure (self-reported) activity-related dyspnoea but cannot replace objectively measured functional capacity.

Functional status measurement in COPD: a review of available methods and their feasibility in primary care.

AIM: Guidelines advocate that improvement in functional status should be a major goal in COPD treatment. Many tools are available to assess aspects of functional status. This review aims to categorize systematically the available tools based on their construct (i.e. what the tool intends to measure) and to rate the tools for use in the primary care setting. METHODS: PubMed was searched with the keywords 'functional status' or 'physical capacity' or 'functional capacity' and 'COPD'. All tools were categorised and rated on their measurement properties, feasibility, and usage in primary care COPD patients. The tools were divided into four constructs - functional capacity, functional performance, functional reserve, and capacity utilisation - and used the following modes of measurement: laboratory tests; semi-laboratory tests; field tests; and patient-reported outcomes. RESULTS: The PubMed search resulted in 364 articles. Thirty-two tools were identified and rated. CONCLUSIONS: In primary care, the 6-minute walking distance test is the most reliable semi-laboratory functional capacity test, but is not very practical. The pedometer is the best functional performance field test. The Medical Research Council (MRC) dyspnoea questionnaire and the functional status domain of the Clinical COPD Questionnaire (CCQ) are the best patient-reported outcome tools to assess functional performance.

COPD depicted - patients drawing their lungs.

BACKGROUND: Given the increasing importance of patient-reported outcomes (PRO) in quality medical care, we examined the value and feasibility of an innovative method for assessing patients' illness perceptions, represented in drawings made by patients with COPD of their lungs. AIM: The aim of our study was: to study patients' representation of COPD as reflected in their drawings of their lungs; and to examine scores on a validated measure that assesses illness perceptions (ie, Brief Illness Perception Questionnaire [B-IPQ]). PATIENTS AND METHODS: One hundred outpatients with COPD, mean age 70 years, selected from a pharmacy database, participated and 98 filled out the B-IPQ. Eighty-seven patients completed the drawing task. RESULTS: The illness perceptions as reflected in the responses to the B-IPQ scales represented a quite optimistic view of COPD and its consequences. The drawings of the lungs reflected a considerable discordance between patients' representations and medically accepted representations of lungs of a person with COPD. CONCLUSION: Assessing illness perceptions in clinical care and research about COPD offers opportunities to identify goals for patient education and self-management. Inviting patients to draw their illness is an innovative and promising approach to assessing PRO.

Health Status and Morbidities in Resident Relatives of Patients With COPD.

OBJECTIVES: Resident relatives of patients with chronic obstructive pulmonary disease (COPD) may play a major role in obtaining a healthy lifestyle for patients. Little is known about resident relatives. This study aimed to compare health status, morbidities, care dependency, and mobility between patients with COPD and their resident relatives. DESIGN: Cross-sectional study. PARTICIPANTS: Stable patients with moderate to very severe COPD (n = 194) and their resident relatives (n = 194) were visited in their home environment. MEASUREMENTS: Post-bronchodilator spirometry was assessed and generic health status was measured using the EuroQol-5 Dimensions and the Assessment of Quality of Life with 8 dimensions. Care dependency was measured using the Care Dependency Scale. Mobility was measured using the Timed "Up and Go" test (TUG). Morbidities (COPD, hypertension, anxiety and depression, obesity, and muscle wasting) were determined using accepted disease cutoff points and/or receiving specific treatment. RESULTS: Age (patients: 66.0 [8.7], resident relatives: 64.8 [9.7]) and gender (male patients: 53%, male resident relatives: 45%) were comparable. Patients had worse generic health status, higher level of care dependency, and worse mobility. 29% of the resident relatives had airflow limitation based on the Tiffeneau index and 19% based on the lower limit of normal, 33% were current smokers, and 92% had at least one chronic condition. Resident relatives more frequently had hypertension (46% versus 69%). CONCLUSION: Resident relatives of patients with COPD are often current smokers and often have undiagnosed morbidities. Although their health status is better compared with patients, their disease management and health behavior should also be considered when advising patients in obtaining a healthier lifestyle and also when involving them as informal caregivers.

Effectiveness of the Assessment of Burden of COPD (ABC) tool on health-related quality of life in patients with COPD: a cluster randomised controlled trial in primary and hospital care.

OBJECTIVE: Assessing the effectiveness of the Assessment of Burden of COPD (ABC) tool on disease-specific quality of life in patients with chronic obstructive pulmonary disease (COPD) measured with the St. George's Respiratory Questionnaire (SGRQ), compared with usual care. METHODS: A pragmatic cluster randomised controlled trial, in 39 Dutch primary care practices and 17 hospitals, with 357 patients with COPD (postbronchodilator FEV1/FVC ratio <0.7) aged ≥40 years, who could understand and read the Dutch language. Healthcare providers were randomly assigned to the intervention or control group. The intervention group applied the ABC tool, which consists of a short validated questionnaire assessing the experienced burden of COPD, objective COPD parameter (eg, lung function) and a treatment algorithm including a visual display and treatment advice. The control group provided usual care. Researchers were blinded to group allocation during analyses. Primary outcome was the number of patients with a clinically relevant improvement in SGRQ score between baseline and 18-month follow-up. Secondary outcomes were the COPD Assessment Test (CAT) and the Patient Assessment of Chronic Illness Care (PACIC; a measurement of perceived quality of care). RESULTS: At 18-month follow-up, 34% of the 146 patients from 27 healthcare providers in the intervention group showed a clinically relevant improvement in the SGRQ, compared with 22% of the 148 patients from 29 healthcare providers in the control group (OR 1.85, 95% CI 1.08 to 3.16). No difference was found on the CAT (-0.26 points (scores ranging from 0 to 40); 95% CI -1.52 to 0.99). The PACIC showed a higher improvement in the intervention group (0.32 points (scores ranging from 1 to 5); 95% CI 0.14 to 0.50). CONCLUSIONS: This study showed that use of the ABC tool may increase quality of life and perceived quality of care. TRIAL REGISTRATION NUMBER: NTR3788; Results.

Tiotropium and Salmeterol in COPD Patients at Risk of Exacerbations: A Post Hoc Analysis from POET-COPD(®).

INTRODUCTION: Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events. The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known. METHODS: A post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD(®)) database. RESULTS: Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk. With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478). For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol. With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968). DISCUSSION: This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk. FUNDING: Boehringer Ingelheim and Pfizer. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00563381.

Effects of Tiotropium on Exacerbations in Patients with COPD with Low or High Risk of Exacerbations: A Post-Hoc Analysis from the 4-Year UPLIFT® Trial.

Background: A history of past exacerbations is a predictor of future events for patients with chronic obstructive pulmonary disease (COPD). Very little is known about the effect of pharmacologic therapies on patients with frequent or infrequent exacerbations. Methods: We conducted a post-hoc analysis of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®)trial database. Patients were classified as having a low risk of exacerbations if they experienced ≤1 exacerbation and no COPD-related hospitalization(s) in the year preceding trial entry or as high risk of exacerbations if they had ≥2 exacerbations (courses of oral steroids/antibiotics) or ≥1 COPD-related hospitalization(s) in the year preceding the trial. Results: In patients at low risk or high risk for exacerbations, compared to placebo, tiotropium significantly reduced: 1) the time to first COPD exacerbation (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.74, 0.88; p <0.0001; HR: 0.89; 95% CI: 0.81, 0.97; p=0.0066, respectively); 2) the number of COPD exacerbations (rate ratio [RR]: 0.79; 95% CI: 0.72, 0.86; p<0.0001; RR: 0.88; 95% CI: 0.81; 0.95; p=0.0009). Furthermore, upon treatment with tiotropium, the proportion of patients transitioning from the low- to the high-risk exacerbations group was statistically lower compared to placebo (RR: 0.78; 95% CI: 0.67, 0.92; p=0.0030) Conclusions: This analysis shows that tiotropium reduces the risk of subsequent exacerbation and also prolongs time to first exacerbation, in both the high- and low-risk exacerbator subgroups. It also decreases the proportion of patients who shift from the low- to the high-risk exacerbations group compared to placebo.

Development of the Assessment of Burden of COPD tool: an integrated tool to measure the burden of COPD.

In deciding on the treatment plan for patients with chronic obstructive pulmonary disease (COPD), the burden of COPD as experienced by patients should be the core focus. It is therefore important for daily practice to develop a tool that can both assess the burden of COPD and facilitate communication with patients in clinical practice. This paper describes the development of an integrated tool to assess the burden of COPD in daily practice. A definition of the burden of COPD was formulated by a Dutch expert team. Interviews showed that patients and health-care providers agreed on this definition. We found no existing instruments that fully measured burden of disease according to this definition. However, the Clinical COPD Questionnaire meets most requirements, and was therefore used and adapted. The adapted questionnaire is called the Assessment of Burden of COPD (ABC) scale. In addition, the ABC tool was developed, of which the ABC scale is the core part. The ABC tool is a computer program with an algorithm that visualises outcomes and provides treatment advice. The next step in the development of the tool is to test the validity and effectiveness of both the ABC scale and tool in daily practice.