Daryl Freeman

Leukotriene Antagonists as First-Line or Add-on Asthma-Controller Therapy

BACKGROUND Most randomized trials of treatment for asthma study highly selected patients under idealized conditions. METHODS We conducted two parallel, multicenter, pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist (LTRA) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist (LABA) as add-on therapy in patients already receiving inhaled glucocorticoid therapy. Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). We randomly assigned patients to 2 years of open-label therapy, under the care of their usual physician, with LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in the first-line controller therapy trial and LTRA (170 patients) or LABA (182 patients) added to an inhaled glucocorticoid in the add-on therapy trial. RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, -0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of -0.11 (95% CI, -0.35 to 0.13) in the first-line controller therapy trial and of -0.11 (95% CI, -0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups. CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients. Equivalence was not proved at 2 years. The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group. (Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others; Controlled Clinical Trials number, ISRCTN99132811.).

Symptom-based questionnaire for identifying COPD in smokers

Background: Symptom-based questionnaires may enhance chronic obstructive pulmonary disease (COPD) screening in primary care. Objectives: We prospectively tested questions to help identify COPD among smokers without prior history of lung disease. Methods: Subjects were recruited via random mailing to primary care practices in Aberdeen, UK, and Denver, Colo., USA. Current and former smokers aged 40 or older with no prior respiratory diagnosis and no respiratory medications in the past year were enrolled. Participants answered questions covering demographics and symptoms and then underwent spirometry with reversibility testing. A study diagnosis of COPD was defined as fixed airway obstruction as measured by postbronchodilator FEV1/FVC <0.70. We examined the ability of individual questions in a multivariate framework to correctly discriminate between persons with and without COPD. Results: 818 subjects completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analysis, which was reduced to 17 items for entry into multivariate regression. Eight items had significant relationships with the study diagnosis of COPD, including age, pack-years, body mass index, weather-affected cough, phlegm without a cold, morning phlegm, wheeze frequency, and history of any allergies. Individual items yielded odds ratios ranging from 0.23 to 12. This questionnaire demonstrated a sensitivity of 80.4 and specificity of 72.0. Conclusions: A simple patient self-administered questionnaire can be used to identify patients with a high likelihood of having COPD, for whom spirometric testing is particularly important. Implementation of this questionnaire could enhance the efficiency and diagnostic accuracy of current screening efforts.

Symptom-Based Questionnaire for Differentiating COPD and Asthma

Background: Many patients with obstructive lung disease (OLD) carry an inaccurate diagnostic label. Symptom-based questionnaires could identify persons likely to need spirometry. Objectives: We prospectively tested questions derived from a comprehensive literature review and an international Delphi panel to help identify chronic OLD (COPD) in persons with prior evidence of OLD. Methods: Subjects were recruited via random mailing to primary-care practices in Aberdeen, Scotland, and Denver, Colorado. Persons aged 40 and older reporting any prior diagnosis of OLD or any respiratory medications in the past year were enrolled. Participants answered 54 questions covering demographics and symptoms and underwent spirometry with reversibility testing. A study diagnosis of COPD was defined by fixed airway obstruction as measured by post-bronchodilator FEV1/FVC <0.70. We examined ability of individual questions in a multivariate framework to discriminate between persons with and without the study diagnosis of COPD. Results: 597 persons completed all investigations and proceeded to analysis. The list of 54 questions yielded 52 items for analyses, which was reduced to 19 items for entry into a multivariate regression model. Nine items had significant relationships with the study diagnosis of COPD, including increased age, pack-years, worsening cough, breathing-related disability or hospitalization, worsening dyspnea, phlegm quantity, cold going to the chest, and receipt of treatment for breathing. Individual items yielded odds ratios ranging from 0.33 to 20.7. This questionnaire demonstrated a sensitivity of 72.0 and a specificity of 82.7. Conclusions: A short, symptom-based questionnaire identifies persons more likely to have COPD among persons with prior evidence of OLD.

Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort.

BACKGROUND Patterns of health-care use and comorbidities present in patients in the period before diagnosis of chronic obstructive pulmonary disease (COPD) are unknown. We investigated these factors to inform future case-finding strategies. METHODS We did a retrospective analysis of a clinical cohort in the UK with data from Jan 1, 1990 to Dec 31, 2009 (General Practice Research Database and Optimum Patient Care Research Database). We assessed patients aged 40 years or older who had an electronically coded diagnosis of COPD in their primary care records and had a minimum of 3 years of continuous practice data for COPD (2 years before diagnosis up to a maximum of 20 years, and 1 year after diagnosis) and at least two prescriptions for COPD since diagnosis. We identified missed opportunites to diagnose COPD from routinely collected patient data by reviewing patterns of health-care use and comorbidities present before diagnosis. We assessed patterns of health-care use in terms of lower respiratory consultations (infective and non-infective), lower respiratory consultations with a course of antibiotics or oral steroids, and chest radiography. If these events did not lead to a diagnosis of COPD, they were deemed to be missed opportunities. This study is registered with ClinicalTrials.gov, number NCT01655667. FINDINGS We assessed data for 38,859 patients. Opportunities for diagnosis were missed in 32,900 (85%) of 38,859 patients in the 5 years immediately preceding diagnosis of COPD; in 12,856 (58%) of 22,286 in the 6-10 years before diagnosis, in 3943 (42%) of 9351 in the 11-15 years before diagnosis; and in 95 (8%) of 1167 in the 16-20 years before diagnosis. Between 1990 and 2009, we noted decreases in the age at diagnosis (0·05 years of age per year, 95% CI 0·03-0·07) and yearly frequency of lower respiratory prescribing consultations (rate ratio 0·982 opportunities per year, 95% CI 0·979-0·985). Prevalence of all comorbidities present at COPD diagnosis increased except for asthma and bronchiectasis, which decreased between 1990 and 2007, from 281 (33·4%) of 842 patients to 451 of 1465 (30·8%) for asthma, and from 53 of 842 (6·3%) to 53 of 1465 (3·6%) for bronchiectasis. In the 2 years before diagnosis, of 6897 patients who had had a chest radiography, only 2296 (33%) also had spirometry. INTERPRETATION Opportunities to diagnose COPD at an earlier stage are being missed, and could be improved by case-finding in patients with lower respiratory tract symptoms and concordant long-term comorbidities. FUNDING UK Department of Health, Research in Real Life.

Earlier diagnosis and earlier treatment of COPD in primary care

Chronic obstructive pulmonary disease (COPD) is a progressive disease that begins many years before a diagnosis is usually made. The need for an early and confirmed diagnosis of COPD is increasingly appreciated by primary care physicians in whose hands the ability to make improvements in early diagnosis largely rests. Case-finding of patients with symptoms of lifestyle limitation is probably the most practical way to achieve early diagnosis. Evidence suggests a burden of early COPD on afflicted people and their families. Early encouragement of smoking cessation, in conjunction with management of symptoms and treating activity limitation and exacerbations by appropriate non-pharmacologic and pharmacologic management at the earliest possible stage, could positively affect the impact and progression of the disease.

Efficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) study

BackgroundClinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease (COPD), and typically had included limitation of concomitant medication. In primary care, which is the most common setting for COPD management, many patients may have milder disease, and also may take a broad range of concomitant medication.MethodsThis randomised, placebo-controlled, parallel-group, 12-week, 44-centre study investigated the efficacy (trough forced expiratory volume in 1 second [FEV1] response) and safety of additional treatment with once-daily tiotropium 18 μg via the HandiHaler® in a primary care COPD population (tiotropium: N = 191, FEV1 = 1.25 L [47.91% predicted]; placebo: N = 183, FEV1 = 1.32 L [49.86% predicted]). Secondary endpoints included: trough forced vital capacity (FVC) response, weekly use of rescue short-acting β-agonist, and exacerbation of COPD (complex of respiratory symptoms/events of >3 days in duration requiring a change in treatment). Treatment effects were determined using non-parametric analysis.ResultsAt Week 12, median improvement in trough FEV1 response with tiotropium versus placebo was 0.06 L (p = 0.0102). The improvement was consistent across baseline treatment and COPD severity. Median improvement in FVC at 2, 6 and 12 weeks was 0.12 L (p < 0.001). The percentage of patients with ≥1 exacerbation was reduced (tiotropium 9.5%; placebo 17.9%; p = 0.0147), independent of disease severity. Rescue medication usage was significantly reduced in the tiotropium group compared with placebo. Adverse event profile was consistent with previous studies.ConclusionTiotropium provides additional benefits to usual primary care management in a representative COPD population.Trial registrationThe identifier is: NCT00274079.

Real-world research and its importance in respiratory medicine

Educational Aims To improve understanding of: The relative benefits and limitations of evidence derived from different study designs and the role that real-life asthma studies can play in addressing limitations in the classical randomised controlled trial (cRCT) evidence base. The importance of guideline recommendations being modified to fit the populations studied and the model of care provided in their reference studies. Key points Classical randomised controlled trials (cRCTs) show results from a narrow patient group with a constrained ecology of care. Patients with “real-life” co-morbidities and lifestyle factors receiving usual care often have different responses to medication which will not be captured by cRCTs if they are excluded by strict selection criteria. Meta-analyses, used to direct guidelines, contain an inherent meta-bias based on patient selection and artificial patient care. Guideline recommendations should clarify where they related to cRCT ideals (in terms of patient populations, medical resources and care received) and could be enhanced through inclusion of evidence from studies designed to better model the populations and care approaches present in routine care. Summary Clinical practice requires a complex interplay between experience and training, research, guidelines and judgement, and must not only draw on data from traditional or classical randomised controlled trials (cRCTs), but also from pragmatically designed studies that better reflect real-life clinical practice. To minimise extraneous variables and to optimise their internal validity, cRCTs exclude patients, clinical characteristics and variations in care that could potentially confound outcomes. The result is that respiratory cRCTs often enrol a small, non-representative subset of patients and overlook the important interplay and interactions between patients and the real world, which can effect treatment outcomes. Evidence from real-life studies (e.g. naturalistic or pragmatic clinical trials and observational studies encompassing healthcare database studies and cohort studies) can be combined with cRCT evidence to provide a fuller picture of intervention effectiveness and realistic treatment outcomes, and can provide useful insights into alternative management approaches in more challenging asthma patients. The Respiratory Effectiveness Group (REG), in collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS), is developing quality appraisal tools and methods for integrating different sources of evidence. A REG/EAACI taskforce aims to help support future guideline developers to avoid a one-size-fits-all approach to recommendations and to tailor the conclusions of their meta-analyses to the populations under consideration.

Long-acting muscarinic antagonist use in adults with asthma: real-life prescribing and outcomes of add-on therapy with tiotropium bromide

Background Randomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care. Methods Medical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001–2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting β2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices. Results Of the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting β2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting β2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) μg/day (P=0.01). Conclusion In this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.

Predicting frequent COPD exacerbations using primary care data

Purpose Acute COPD exacerbations account for much of the rising disability and costs associated with COPD, but data on predictive risk factors are limited. The goal of the current study was to develop a robust, clinically based model to predict frequent exacerbation risk. Patients and methods Patients identified from the Optimum Patient Care Research Database (OPCRD) with a diagnostic code for COPD and a forced expiratory volume in 1 second/forced vital capacity ratio <0.7 were included in this historical follow-up study if they were ≥40 years old and had data encompassing the year before (predictor year) and year after (outcome year) study index date. The data set contained potential risk factors including demographic, clinical, and comorbid variables. Following univariable analysis, predictors of two or more exacerbations were fed into a stepwise multivariable logistic regression. Sensitivity analyses were conducted for subpopulations of patients without any asthma diagnosis ever and those with questionnaire data on symptoms and smoking pack-years. The full predictive model was validated against 1 year of prospective OPCRD data. Results The full data set contained 16,565 patients (53% male, median age 70 years), including 9,393 patients without any recorded asthma and 3,713 patients with questionnaire data. The full model retained eleven variables that significantly predicted two or more exacerbations, of which the number of exacerbations in the preceding year had the strongest association; others included height, age, forced expiratory volume in 1 second, and several comorbid conditions. Significant predictors not previously identified included eosinophilia and COPD Assessment Test score. The predictive ability of the full model (C statistic 0.751) changed little when applied to the validation data set (n=2,713; C statistic 0.735). Results of the sensitivity analyses supported the main findings. Conclusion Patients at risk of exacerbation can be identified from routinely available, computerized primary care data. Further study is needed to validate the model in other patient populations.

A pragmatic single-blind randomised controlled trial and economic evaluation of the use of leukotriene receptor antagonists in primary care at steps 2 and 3 of the national asthma guidelines (ELEVATE study).

This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 21. See the HTA programme website for further project information.