[Show abstract][Hide abstract] ABSTRACT: Real-world data on the benefit/risk profile of medicines is needed, particularly in patients who are ineligible for randomised controlled trials conducted for registration purposes. This paper describes the methodology and source data verification which enables the conduct of pre-licensing clinical trials of COPD and asthma in the community using the electronic medical record (EMR), NorthWest EHealth linked database (NWEH-LDB) and alert systems.
Dual verification of extracts into NWEH-LDB was performed using two independent data sources (Salford Integrated Record [SIR] and Apollo database) from one primary care practice in Salford (N = 3504). A feasibility study was conducted to test the reliability of the NWEH-LDB to support longitudinal data analysis and pragmatic clinical trials in asthma and COPD. This involved a retrospective extraction of data from all registered practices in Salford to identify a cohort of patients with a diagnosis of asthma (aged ≥18) and/or COPD (aged ≥40) and ≥2 prescriptions for inhaled bronchodilators during 2008. Health care resource utilisation (HRU) outcomes during 2009 were assessed. Exacerbations were defined as: prescription for oral corticosteroids (OCS) in asthma and prescription of OCS or antibiotics in COPD; and/or hospitalisation for a respiratory cause.
Dual verification demonstrated consistency between SIR and Apollo data sources: 3453 (98.6%) patients were common to both systems; 99.9% of prescription records were matched and of 29,830 diagnosis records, one record was missing from Apollo and 272 (0.9%) from SIR. Identified COPD patients were also highly concordant (Kappa coefficient = 0.98). A total of 7981 asthma patients and 4478 COPD patients were identified within the NWEH-LDB. Cohort analyses enumerated the most commonly prescribed respiratory medication classes to be: inhaled corticosteroids (ICS) (42%) and ICS plus long-acting β2-agonist (LABA) (40%) in asthma; ICS plus LABA (55%) and long-acting muscarinic antagonists (36%) in COPD. During 2009 HRU was greater in the COPD versus asthma cohorts, and exacerbation rates in 2009 were higher in patients who had ≥2 exacerbations versus ≤1 exacerbation in 2008 for both asthma (137.5 vs. 20.3 per 100 person-years, respectively) and COPD (144.6 vs. 41.0, respectively).
Apollo and SIR data extracts into NWEH-LDB showed a high level of concordance for asthma and COPD patients. Longitudinal data analysis characterized the COPD and asthma populations in Salford including medications prescribed and health care utilisation outcomes suitable for clinical trial planning.
BMC Medical Informatics and Decision Making 12/2015; 15(1). DOI:10.1186/s12911-015-0132-z · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach.
European Respiratory Journal 09/2015; DOI:10.1183/13993003.00779-2015 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy.
Patients with chronic obstructive pulmonary disease (COPD), ≥40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 μg/vilanterol 25 μg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data.
The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD.
Clinicaltrials.gov identifier NCT01551758 .
Respiratory research 09/2015; 16(1):101. DOI:10.1186/s12931-015-0267-6 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: We tested the hypotheses that fibrinogen and α1-antitrypsin are observationally and genetically associated with exacerbations in COPD.
METHODS: We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003-2013), of whom 6857 were genotyped for FGB -455 (rs1800790, G>A) and FGB -448 (rs4220, G>A) and had plasma fibrinogen measured. Furthermore, 13 405 individuals were genotyped for the SERPINA1 S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma α1-antitrypsin. Exacerbations were defined as hospital admissions or treatments with systemic corticosteroids. We studied observational associations between plasma measurements and exacerbations in Cox regression analyses, associations between genotypes and exacerbations in logistic regression analyses and associations between genetically determined plasma levels and exacerbations in instrumental variable analyses.
RESULTS: Elevated fibrinogen and α1-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p<0.001) and 1.18 (1.11 to 1.25, p<0.001), respectively, per SD increase. Presence of the Z-allele was associated with increased odds of exacerbations, OR=1.25 (1.05 to 1.48, p=0.01), as was α1-antitrypsin level genetically lowered by the Z-allele, OR=1.07 (1.02 to 1.13, p=0.004), per SD decrease. Fibrinogen elevating genotypes, FGB -455 (AA) and FGB -448 (AA), were not associated with exacerbations, OR=0.96 (0.73 to 1.25, p=0.77) and OR=1.01 (0.75 to 1.33, p=0.90), respectively, and neither was genetically elevated fibrinogen level, OR=1.11 (0.76 to 1.63, p=0.58) per SD increase.
CONCLUSIONS: Fibrinogen and α1-antitrypsin were observationally associated with increased risk of exacerbations. However, genetically, fibrinogen per se was not associated with exacerbations, while lowered α1-antitrypsin was associated with increased odds of exacerbations.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms.
We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end.
Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure.
Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).
New England Journal of Medicine 07/2015; 373(2):111-22. DOI:10.1056/NEJMoa1411532 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Early morning symptoms (EMS) in people with COPD are associated with poor health, impaired activities and increased exacerbation risk. We describe the development and preliminary validation of the Manchester Early Morning Symptom Index (MEMSI) to quantify EMS in COPD.
Focus groups and cognitive debriefing with patients with COPD were used to develop the potential item list, followed by a cross-sectional study to finalise the items for inclusion. In addition to test-retest reliability, comparisons with the St George's Respiratory Questionnaire-C (SGRQ-C), modified Medical Research Council Dyspnoea Scale, Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) and Hospital Anxiety and Depression Scale (HADS) evaluated construct validity. Hierarchical methods informed item deletion and Rasch analysis was applied to assess scale unidimensionality.
23 items were identified from the focus groups and debriefings. The cross-sectional study involved 203 patients with COPD (mean age 64.7 SD 7.5 years, male 63%, Global Initiative for Chronic Obstructive Lung Disease (GOLD): 1:14% 2:41% 3:25% 4: 7%). 13 items were removed during item reduction. MEMSI contains 10 items, demonstrates good overall fit to the Rasch model (χ(2) p=0.26) and item score distribution; excellent reliability (Person Separation Index: 0.91) and good test-retest repeatability (r=0.82). It correlates with the SGRQ-C (r=0.73), FACIT-F (r=-0.65) and HADS (r=0.53-0.54) indicating good construct validity.
MEMSI is a reliable and valid unidimensional measure of EMS for patients with COPD. It is simple to use and score supporting its suitability for research and clinical use. Work is underway to determine the minimal clinical important difference and cross-cultural validity.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Recently, several proteins of the extracellular matrix have been characterised as active contributors to allergic airway disease. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein abundant in the lung, whose biological functions remain poorly understood. In the current study we investigated the role of MFAP4 in experimental allergic asthma.
MFAP4-deficient mice were subjected to alum/ovalbumin and house dust mite induced models of allergic airway disease. In addition, human healthy and asthmatic primary bronchial smooth muscle cell cultures were used to evaluate MFAP4-dependent airway smooth muscle responses.
MFAP4 deficiency attenuated classical hallmarks of asthma, such as eosinophilic inflammation, eotaxin production, airway remodelling and hyperresponsiveness. In wild-type mice, serum MFAP4 was increased after disease development and correlated with local eotaxin levels. MFAP4 was expressed in human bronchial smooth muscle cells and its expression was upregulated in asthmatic cells. Regarding the underlying mechanism, we showed that MFAP4 interacted with integrin αvβ5 and promoted asthmatic bronchial smooth muscle cell proliferation and CCL11 release dependent on phosphatidyloinositol-3-kinase but not extracellular signal-regulated kinase pathway.
MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Despite massive investments in development of novel treatments for heterogeneous diseases such as Chronic Obstructive Pulmonary Disease (COPD), the resources spent have only benefitted a fraction of the population treated. Personalized Health Care to guide selection of a suitable patient population already in the clinical development of new compounds could offer a solution. In this review, we discuss past successes and failures in drug development and biomarker research in COPD. We describe research in COPD phenotypes, and the required characteristics of a suitable biomarker for identifying patients at higher risk of progression. We review the role of extra-cellular matrix proteins found to be upregulated in COPD. Novel biomarkers of connective tissue remodeling which may provide added value for a personalized approach by detecting subgroups of patients with active disease suitable for pharmacological intervention are discussed.
[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: Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that likely includes clinically relevant subgroups. Objectives: To identify subgroups of COPD in ECLIPSE subjects using unsupervised cluster analysis and to assess clinically meaningful outcomes of the clusters during 3 years of longitudinal follow-up. Methods: Factor analysis was used to reduce 41 variables determined at recruitment in 2,164 COPD patients to 13 main factors, and the variables with the highest loading were used for unsupervised cluster analysis. Clusters were then evaluated for their relationship with clinically meaningful outcomes during 3 years of follow-up. The relationships among clinical parameters were evaluated within clusters. Measurements and Main Results: Five subgroups were distinguished using cross-sectional clinical features. Importantly, these groups differed with regard to outcomes. Cluster A included milder patients and had fewer deaths and hospitalizations. Cluster B had less systemic inflammation at baseline but had notable changes in health status and emphysema extent. Cluster C had many comorbidities, evidence of systemic inflammation and the highest mortality. Cluster D had low FEV1, severe emphysema and the highest exacerbation and COPD hospitalization rate. Cluster E was intermediate for most variables and may represent a mixed group that includes further clusters. The relationships among clinical variables within clusters differed from that in the entire COPD population. Conclusions: Unsupervised cluster analysis using baseline data in ECLIPSE identified five COPD subgroups that differ in outcomes and inflammatory biomarkers and show different relationships between clinical parameters, suggesting the clusters represent clinically and biologically different subtypes of COPD.