[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Patients with COPD are characterised by a reduced health status, which can be easily assessed by the COPD Assessment Test (CAT). Previous studies show that health status can be worsened by the presence of comorbidities. However, the impact of cardiovascular comorbidities on health status as assessed with CAT is not sufficiently investigated. Therefore, the current study has the following objectives: (1) to study the clinical, (patho)physiological and psychosocial determinants of the CAT, and impact of previously established and/or newly diagnosed cardiovascular comorbidities on health status in tertiary care patients with COPD; (2) to assess the effects of pulmonary rehabilitation on CAT scores in patients with COPD; (3) to develop reference values for the CAT in Dutch elderly patients without COPD; and (4) to validate the CAT in a broad sample of Dutch patients with COPD.
METHODS AND ANALYSIS: The COPD, Health status and Comorbidities (Chance) study is a monocentre study consisting of an observational cross-sectional part and a longitudinal part. Demographic and clinical characteristics will be assessed in primary care, secondary care and tertiary care patients with COPD, and in patients without COPD. To assess health status, the CAT, Clinical COPD Questionnaire (CCQ) and St George's Respiratory Questionnaire (SGRQ) will be used. The longitudinal part consists of a comprehensive pulmonary rehabilitation programme in 500 tertiary care patients. For the cross-sectional part of the study, 150 patients without COPD, 100 primary care patients and 100 secondary care patients will be assessed during a single home visit.
ETHICS AND DISSEMINATION: The Medical Ethical Committee of the Maastricht University Medical Centre+ (MUMC+), Maastricht, the Netherlands (METC 11-3-070), has approved this study. The study has been registered at the Dutch Trial Register (NTR 3416).
BMJ Open 07/2015; 5(7). DOI:10.1136/bmjopen-2014-007536 · 2.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality, and resource use worldwide. The goal of this Official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management.
Clinicians, researchers, and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarized, and then salient knowledge gaps were identified.
Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus.
Great strides have been made in the diagnosis, assessment, and management of COPD as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS Research Statement highlights the types of research that leading clinicians, researchers, and patient advocates believe will have the greatest impact on patient-centered outcomes.
American Journal of Respiratory and Critical Care Medicine 04/2015; 191(7):e4-e27. DOI:10.1164/rccm.201501-0044ST · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
A meta-analysis of published data was conducted to investigate the overall risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer (NSCLC) who were receiving vandetanib.
A computerized search through electronic databases, including PubMed and Embase (until Dec 2014), was performed to obtain eligible randomized controlled trials (RCTs) that compared hypertension and/or QTc prolongation profile of vandetanib alone or plus chemotherapy with control groups (placebo, single targeted therapy, chemotherapy, or a combination of them) in patients with advanced NSCLC. The outcome measures were the overall risks of hypertension and QTc prolongation. Relative risk (RR) and 95 % confidence interval (CI) were calculated and pooled using a random effects model.
A total of nine RCTs, which involved 4813 patients, were enrolled in the present study. A significant increase in risk was observed for all-grade hypertension (RR 5.58; 95 % CI 4.16 to 7.48; P < 0.00001) and grade ≥3 hypertension (RR 4.79; 95 % CI 2.31 to 9.93; P < 0.0001) in advanced NSCLC patients who were receiving vandetanib compared with the controls. Moreover, vandetanib significantly prolonged all-grade QTc interval (RR 7.90; 95 % CI 4.03 to 15.50; P < 0.00001) and grade ≥3 QTc interval (RR 3.12; 95 % CI 1.01 to 9.63; P = 0.05).
Current evidence showed that significant risks in developing hypertension and QTc prolongation exist in advanced NSCLC patients who were receiving vandetanib. Thus, appropriate monitoring and management of these events are recommended.
[Show abstract][Hide abstract] ABSTRACT: Three long-acting muscarinic antagonists (LAMAs) are now available in Europe, providing clinicians and patients with a choice of interventions, which is important in COPD, which is clinically a heterogeneous disease. The first LAMA, tiotropium, has been widely used over the last decade as a once-daily maintenance therapy in stable COPD to improve patients' health-related quality of life and to reduce the risk of exacerbations. Administered via the HandiHaler (R) device, it is safe and well tolerated. Another new once-daily LAMA, glycopyrronium, has also been shown to improve health status and reduce exacerbations, and is well tolerated. The subject of this review is a third LAMA, aclidinium bromide, which was approved as a twice-daily maintenance bronchodilator treatment. In the pivotal Phase III clinical trials, patients receiving aclidinium achieved significantly greater improvements in lung function, reductions in breathlessness, and improvements in health status compared with placebo, for up to 24 weeks. In continuation studies, these improvements were sustained for up to 52 weeks. Pooled data showed exacerbation frequency was significantly reduced with aclidinium versus placebo. Preclinical and pharmacological studies demonstrating low systemic bioavailability and a low propensity to induce cardiac arrhythmias were translated into a favorable tolerability profile in the clinical trial program - the adverse event profile of aclidinium was similar to placebo, with a low incidence of anticholinergic and cardiac adverse events. While additional studies are needed to evaluate its full clinical potential, aclidinium is an important part of this recent expansion of LAMA therapeutic options, providing clinicians and patients with an effective and well-tolerated COPD treatment.
International Journal of COPD 03/2015; 10:677. DOI:10.2147/COPD.S76520 · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Previous studies on chronic bronchitis (CB) have used varying definitions. We sought to compare an alternative CB definition using the St. George's Respiratory Questionnaire, a commonly used assessment tool, with the classic definition and to investigate if it had independent or additive value. Methods: We analyzed data from 4513 GOLD 1-4 subjects in the COPDGene cohort. We compared the classic definition of CB with the SGRQ definition, defined by their answers to the questions about both cough and phlegm. We compared the Classic CB+ vs. CB- groups, and the SGRQ CB+ and CB- groups. We also analyzed the cohort split into four groups: Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB-, Classic CB-/SGRQ CB+, Classic CB-/SGRQ CB-. Results: 26.1% were Classic CB+, whereas 39.9% were SGRQ CB+. When the SGRQ definition was compared with the Classic CB definition, using this as the gold standard, the SGRQ CB definition had a sensitivity and specificity of 0.87 and 0.77, respectively. The SGRQ CB+ and Classic CB+ groups were strikingly similar with more respiratory symptoms, exacerbations, worse lung function, and greater airway wall thickness. In addition, the Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB-, Classic CB-/SGRQ CB+ groups shared similar characteristics as well. Conclusions: The SGRQ CB definition identifies more subjects with chronic cough and sputum that share a similar phenotype identified by the Classic CB definition. The addition of the SGRQ CB definition to the classic one can be used to identify more COPD patients at risk for poor outcomes.
[Show abstract][Hide abstract] ABSTRACT: Rationale: Radiographically-confirmed pneumonia risk has not been assessed with inhaled corticosteroid use in chronic obstructive pulmonary disease (COPD). Objectives: To determine the incidence of pneumonia, risk factors and clinical attributes with inhaled fluticasone furoate in COPD patients with an exacerbation history. Methods: Two replicate, 1-year, double-blind clinical trials enrolled COPD subjects with moderate to very severe airflow limitation and at least one exacerbation in the prior year. Subjects were randomized 1:1:1:1 to receive inhaled once-daily vilanterol 25 µg or vilanterol 25 µg combined with 50 µg, 100 µg, or 200 µg fluticasone furoate. Subjects were required to have a chest radiograph at screening and within 48 hours of any suspected pneumonia or exacerbation. Measurements and Main Results: Of 3255 randomized subjects, 205 pneumonia events occurred in 181 subjects. Chest imaging was available for 195 (95%) of these events. Chest radiographs were also obtained for 1793 (70%) of the 2545 moderate and severe exacerbations. For vilanterol alone and the combination with 50 µg, 100 µg, or 200 µg fluticasone furoate, reported pneumonia incidence was 3%, 6%, 6% and 7%, respectively. However, for events with compatible parenchymal infiltrates, respective incidences were 2%, 4%, 4% and 5%. Factors associated with at least a two-fold increase in the risk of pneumonia with FF/VI were being a current smoker, having prior pneumonia, BMI < 25kg/m2, and severe airflow limitation. Conclusions: Although the incidence of pneumonia is low, radiographically-confirmed pneumonia risk is increased with inhaled FF/VI, although lower than investigator-defined rates. Clinical trial registered with clinicaltrials.gov NCT01009463 (HZC102871); NCT01017952 (HZC102970).
[Show abstract][Hide abstract] ABSTRACT: Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed.
In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (>=40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 >=30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 mug (n = 385) or 400/6 mug (n = 381), aclidinium 400 mug (n = 385), formoterol 12 mug (n = 384) or placebo (n = 194) BID via Genuair(R)/Pressair(R)a.
At Week 24, aclidinium/formoterol 400/12 mug and 400/6 mug lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 . 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 mug and 400/6 mug provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy.
Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD.Trial registration: ClinicalTrials.gov: NCT01462942.
BMC Pulmonary Medicine 11/2014; 14(1):178. DOI:10.1186/1471-2466-14-178 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT ¿ Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.Methods
This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N¿=¿235, US) and two 3-month (N¿=¿749; N¿=¿597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset.ResultsIn each study, RS-Total score was internally consistent (Cronbach ¿) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman¿s rho; p¿<¿0.01, all comparisons listed here): FEV1% predicted (¿0.19, ¿0.14, ¿0.15); St. George¿s Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (¿0.30, ¿0.14) and incremental shuttle walk (ISWT) (¿0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p¿<¿0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p¿<¿0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.Conclusions
Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.Trial registrationMPEX: NCT00739648; AZ1: NCT00949975; AZ 2: NCT01023516.
Respiratory Research 10/2014; 15(1):124. DOI:10.1186/s12931-014-0124-z · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Lung volume reduction surgery improves quality of life, exercise capacity, and survival in selected patients but is accompanied by significant morbidity. Bronchoscopic approaches may provide similar benefits with less morbidity. Methods: In a randomized, sham procedure controlled, double-blind trial, 277 subjects were enrolled at 36 centers. Patients had emphysema, airflow obstruction, hyperinflation, and severe dyspnea. The primary effectiveness measure was a significant improvement in disease-related quality of life (St. George's Respiratory Questionnaire) and changes in lobar lung volumes. The primary safety measure was a comparison of serious adverse events. Results: There were 6/121 (5.0%) responders in the treatment group at 6 months, significantly >1/134 (0.7%) in the control group [Bayesian credible intervals (BCI), 0.05%, 9.21%]. Lobar volume changes were significantly different with an average decrease in the treated lobes of -224mL compared with -17mL for the control group (BCI, -272, -143). The proportion of responders in St. George's Respiratory Questionnaire was not greater in the treatment group. There were significantly more subjects with a serious adverse event in the treatment group (n=20 or 14.1%) compared with the control group (n=5 or 3.7%) (BCI, 4.0, 17.1), but most were neither procedure nor device related. Conclusions: This trial had technical and statistical success but partial-bilateral endobronchial valve occlusion did not obtain clinically meaningful results. Safety results were acceptable and compare favorably to lung volume reduction surgery and other bronchial valve studies. Further studies need to focus on improved patient selection and a different treatment algorithm.
Journal of Bronchology and Interventional Pulmonology 10/2014; 21(4):288-297. DOI:10.1097/LBR.0000000000000110
[Show abstract][Hide abstract] ABSTRACT: The frequency and impact of exacerbations identified using healthcare resource utilisation (HCRU) or the EXAcerbations of Chronic pulmonary disease Tool (EXACT) were compared prospectively in a 24-week, phase III trial (ATTAIN). Patients with moderate-to-severe chronic obstructive pulmonary disease received twice-daily aclidinium 200 μg, aclidinium 400 μg or placebo. All HCRU events were reported to physicians. "EXACT-identified" events were categorised as "EXACT-reported" (detected by EXACT and reported to the physician) and "EXACT-unreported" (detected but not reported). Health status was measured using the St George's Respiratory Questionnaire (SGRQ). Annualised EXACT-identified event rates were higher in all study arms (placebo 1.39, aclidinium 200 μg 1.00 and aclidinium 400 μg 0.98 per patient per year) versus HCRU (placebo 0.60, aclidinium 200 μg 0.43 and aclidinium 400 μg 0.40 per patient per year). Concordance between methods was low (kappa 0.16). Aclidinium reduced EXACT-identified events (rate ratio versus placebo: aclidinium 200 μg 0.72 and aclidinium 400 μg 0.71; both p<0.05); HCRU events were similarly reduced. At week 24, SGRQ scores improved (-6.6 versus baseline) in patients with no event during weeks 1-12; improvements were significantly smaller in patients with HCRU events (-3.4; p = 0.036) or EXACT-unreported events (-3.0; p = 0.002). Unreported events were more frequent than reported events. Both had similar negative impact on health status. Aclidinium reduced the frequency of both types of event.
European Respiratory Journal 09/2014; 44(5). DOI:10.1183/09031936.00038814 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
The tradition classification of the severity of COPD, based on spirometry, fails to encompass the heterogeneity of the disease. The COPD assessment test (CAT), a multi-dimensional, patient-filled questionnaire, assesses the overall health status of patients, and is recommended as part of the assessment of individuals with COPD. However, information regarding the range of values for the test in a non-COPD population (normative values) is limited, and consequently, knowledge regarding the optimal cut-off, and the minimum clinically important difference (MCID) for the test remain largely empirical.
CanCOLD is a population-based multi-center cohort study conducted across Canada, the methodology of which is based on the international BOLD initiative. The study includes subjects with COPD, at-risk individuals who smoke, and healthy control subjects. CAT questionnaires were administered at baseline to all subjects. Among non-COPD subjects, normative values for the CAT questionnaire, and psychometric properties of the test were characterized. Predictors of high CAT scores were identified using multivariable logistic regression.
Of the 525 non-COPD subjects enrolled, 500 were included in the analysis. Mean FEV1/FVC ratio among the 500 included subjects was 0.77 (SD 0.49); the mean predicted FEV1 was 99.38% (SD 16.88%). The overall mean CAT score was 6 (SD 5.09); scores were higher among females (6.43, SD 5.59), and subjects over 80 years of age (mean 7.58, SD 6.82). Cronbach alpha for the CAT was 0.79, suggesting a high internal consistency for the test. A score of 16 was the 95th percentile for the population, and 27 subjects (5.4%) were found to have a CAT score > =16. Current smoking (aOR 3.41, 95% CI 1.05, 11.02), subject-reported physician-diagnosed asthma (aOR 7.59, 95% CI 2.71, 21.25) and musculoskeletal disease (aOR 4.09, 95% CI 1.72, 9.71) were found to be significantly associated with a score ≥16.
The characterization of CAT scores in the general population will be useful for norm-based comparisons. Longitudinal follow-up of these subjects will help in the optimization of cut-offs for the test.
Respiratory Research 06/2014; 15(1):68. DOI:10.1186/1465-9921-15-68 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and objectives
Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) commonly coexist and share common risk factors. The prevalence of COPD in outpatients with a smoking history and CVD in Japan is unknown. The aim of this study was to determine the proportion of Japanese patients with a smoking history being treated for CVD who have concurrent airflow limitation compatible with COPD. A secondary objective was to test whether the usage of lung function tests performed in the clinic influenced the diagnosis rate of COPD in the patients identified with airflow limitation.
In a multicenter observational prospective study conducted at 17 centers across Japan, the prevalence of airflow limitation compatible with COPD (defined as forced expiratory volume (FEV)1/FEV6 <0.73, by handheld spirometry) was investigated in cardiac outpatients ≥40 years old with a smoking history who routinely visited the clinic for their CVD. Each patient completed the COPD Assessment Test prior to spirometry testing.
Data were available for 995 patients with a mean age of 66.6±10.0 years, of whom 95.5% were male. The prevalence of airflow limitation compatible with COPD was 27.0% (n=269), and 87.7% of those patients (n=236) did not have a prior diagnosis of COPD. The prevalence of previously diagnosed airflow limitation was higher in sites with higher usage of lung function testing (14.0%, 15.2% respectively) compared against sites where it is performed seldom (11.1%), but was still low.
The prevalence of airflow limitation in this study indicates that a quarter of outpatients with CVD have COPD, almost all of whom are undiagnosed. This suggests that it is important to look routinely for COPD in CVD outpatients.
International Journal of COPD 05/2014; 9:563-8. DOI:10.2147/COPD.S59962 · 3.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011 consensus report proposed a new classification system, incorporating symptoms with future risk, in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized it could be applied to Japanese COPD patients.
We previously analyzed clinical factors related to 5-year mortality in 150 male outpatients with COPD. We reviewed the data and reanalyzed the relationships between the new GOLD classification and various outcomes including mortality.
There were 51 (34.0%), 12 (8.0%), 57 (38.0%), and 30 (20.0%) patients in GOLD A (forced expiratory volume in 1s [FEV1]≥50% predicted and modified Medical Research Council [mMRC] 0-1), GOLD B (FEV1≥50% predicted and mMRC≥2), GOLD C (FEV1<50% predicted and mMRC 0-1), and GOLD D (FEV1 <50% predicted and mMRC≥2), respectively. The GOLD 2011 classification correlated significantly with exercise capacity and multi-dimensional disease staging. Cox proportional hazards analysis revealed that, among several methods categorizing symptoms, the GOLD A-D classification was significantly associated with mortality (p=0.0055).
Although the relative number of patients in each category of the combined COPD assessment classification depended on the choice of symptom measures, the categories defined by the mMRC scale (score 0-1 versus ≥2) were most useful for future risk assessed as mortality. GOLD A had the lowest mortality, followed by GOLD B and C, and D had the highest mortality. Exercise capacity was also stratified by the new GOLD classification.
[Show abstract][Hide abstract] ABSTRACT: The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores.
An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients' reports, physicians' records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed.
The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients.
Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized.Trial registration: Clinical trial registered with UMIN (UMIN000003470).
Respiratory research 02/2014; 15(1):13. DOI:10.1186/1465-9921-15-13 · 3.09 Impact Factor