Methods for external control groups for single arm trials or long-term uncontrolled extensions to randomized clinical trials.

PURPOSE: Clinical trials compare outcomes among patients receiving study treatment with comparators drawn from the same source. These internal controls are missing in single arm trials and from long-term extensions (LTE) of trials including only the treatment arm. An external control group derived from a different setting is then required to assess safety or effectiveness. METHODS: We present examples of external control groups that demonstrate some of the issues that arise and make recommendations to address them through careful assessment of the data source fitness for use, design, and analysis steps. RESULTS: Inclusion and exclusion criteria and context that produce a trial population may result in trial patients with different clinical characteristics than are present in an external comparison group. If these differences affect the risk of outcomes, then a comparison of outcome occurrence will be confounded. Further, patients who continue into LTE may differ from those initially entering the trial due to treatment effects. Application of appropriate methods is needed to make valid inferences when such treatment or selection effects are present. Outcome measures in a trial may be ascertained and defined differently from what can be obtained in an external comparison group. Differences in sensitivity and specificity for identification or measurement of study outcomes leads to information bias that can also invalidate inferences. CONCLUSION: This review concentrates on threats to the valid use of external control groups both in the scenarios of single arm trials and LTE of randomized controlled trials, along with methodological approaches to mitigate them.

Data linkage in pharmacoepidemiology: A call for rigorous evaluation and reporting.

PURPOSE: The purpose of this paper is to provide guidance on the evaluation of data linkage quality through the development of a checklist for reporting key elements of the linkage process. METHODS: Responding to a call for manuscripts from the International Society for Pharmacoepidemiology (ISPE), a working group including international representation from the academic, industry, and contract research, and regulatory sectors was formed to develop a checklist for evaluation of data linkage performance and reporting data linkage specifically for pharmacoepidemiologic research. This checklist expands on the reporting of studies conducted using observational routinely collected health data specific to pharmacoepidemiology (RECORD-PE) guidelines. RESULTS: A key aspect of data linkage evaluation for pharmacoepidemiology is to articulate how a linkage process was performed and its accuracy in terms of validation and verification of the resulting linked data. This study generates a checklist, which covers domains including data sources, linkage variables, linkage methods, linkage results, and linkage evaluation. For each domain, specific recommendations provide a clear and transparent assessment of the linkage process. CONCLUSIONS: Linking data sources can help to enrich analytic databases to more accurately define study populations, enable adjustment for confounding, and improve the capture of health outcomes. Clear and transparent reporting of data linkage processes will help to increase confidence in the evidence generated from these data by allowing researchers and end users to critically assess the potential for bias owing to the data linkage process.

Chronic obstructive pulmonary disease exacerbation episodes derived from electronic health record data validated using clinical trial data.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF). METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap. RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap. CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

The feasibility of using multiple databases to study rare outcomes: the potential effect of long-acting beta agonists with inhaled corticosteroid therapy on asthma mortality.

PURPOSE: Long-acting beta agonists (LABAs) when used without concomitant inhaled corticosteroids (ICS) increase the risk of asthma-related deaths, but the effect on asthma-related death of LABA used in combination with ICS therapy is unknown. To address this question, we explored the feasibility of conducting an observational study using multiple US health care data sources. METHODS: Retrospective cohort study to evaluate the likelihood of getting an upper 95% confidence limit ≤1.4 for the asthma mortality rate ratio and ≤0.40 per 10 000 person-years for the mortality rate difference, assuming no effect of new use of combined LABA + ICS (versus non-LABA maintenance therapy) on asthma mortality. Ten research institutions executed centrally distributed analytic code based on a standard protocol using an extracted (2000-2010) persistent asthma cohort (asthma diagnosis and ≥4 asthma medications in 12 months). Pooled results were analyzed by the coordinating center. Asthma deaths were ascertained by linkage with the National Death Index. RESULTS: In a cohort of 994 627 persistent asthma patients (2.4 million person-years; 278 asthma deaths), probabilities of the upper 95% confidence limit for effect estimates being less than targeted values, assuming a null relation, were about 0.05. Modifications in cohort and exposure definitions increased exposed person-time and outcome events, but study size remained insufficient to attain study goals. CONCLUSIONS: Even with 10 data sources and a 10-year study period, the rarity of asthma deaths among patients using certain medications made it infeasible to study the association between combined LABA + ICS and asthma mortality with our targeted level of study precision. Copyright © 2016 John Wiley & Sons, Ltd.

Noncommunicable Lung Disease in Sub-Saharan Africa. A Community-based Cross-Sectional Study of Adults in Urban Malawi.

RATIONALE: Noncommunicable diseases are major causes of morbidity and mortality in sub-Saharan Africa (sSA). Valid burden of disease estimates are lacking for noncommunicable lung disease in sSA. OBJECTIVES: We performed a community-based survey to determine the prevalence of chronic lung disease among adults 18 years or older in Malawi, using American Thoracic Society standard spirometry, internationally validated respiratory symptom and exposure questionnaires, and an assessment of HIV status. METHODS: An age- and sex-stratified random sample of 2,000 adults was taken from the population of the Chilomoni district of Blantyre, Malawi. Fieldworkers collected questionnaire data, conducted HIV testing, and performed pre- and post-bronchodilator spirometry on eligible participants. Survey-weighted population prevalence estimates of respiratory symptoms and spirometric abnormalities were computed, and bivariate and multivariable regression were used to identify associated variables. MEASUREMENTS AND MAIN RESULTS: Questionnaire data, HIV status, and standard spirometry were obtained from 1,059, 933, and 749 participants, respectively. Current respiratory symptoms, exposure to biomass, and ever-smoking were reported by 11.8, 85.2, and 10.4% of participants, respectively. HIV prevalence was 24.2%. Moderate to severe airway obstruction was seen in 3.6%. The prevalence of spirometric restriction was 38.6% using National Health and Nutrition Examination Survey III reference ranges and 9.0% using local reference ranges. Age was positively associated with obstruction, whereas low body mass index was associated with restriction. CONCLUSIONS: More than 40% of the Malawian adults in our urban population sample had abnormal lung function (mostly restrictive) in the context of widespread exposure to biomass smoke and a high prevalence of HIV. These findings potentially have major public health implications for Malawi and the broader sSA region.

Physician perspectives on the burden and management of asthma in six countries: The Global Asthma Physician Survey (GAPS).

BACKGROUND: Despite recognition of asthma as a growing global issue and development of global guidelines, asthma treatment practices vary between countries. Several studies have reported patients' perspectives on asthma control. This study presents physicians' perspectives and strategies for asthma management. METHODS: Physicians seeing ≥4 adult patients with asthma per month in Australia, Canada, China, France, Germany, and Japan were surveyed (N=1809; ≈300 per country). A standardised questionnaire was developed for this study and administered by telephone, online or face-to-face. Statistics were weighted to account for the sampling scheme. RESULTS: Physicians estimated that 71% of their adult patients received maintenance medication, with adherence monitored by 76-97% of physicians. Perceived major barriers to patient adherence included: patients taking treatment as needed; acceptance of symptoms; and patients not perceiving treatment benefits. Written action plans (37%) and technology (15%) were seldom employed by physicians to aid patients' asthma management. Physicians rarely (10%) used validated patient-reported questionnaires to monitor asthma control, instead monitoring selected symptoms, exacerbations, and/or lung function measurements. Awareness of single maintenance and reliever therapy (SMART/MART) varied among countries (56-100%); although most physicians (72%) had prescribed SMART/MART, the majority (91%) co-prescribed a short-acting bronchodilator at least some of the time. CONCLUSIONS: These results show that physicians generally do not employ standardised tools to monitor asthma control or to manage its treatment and that despite high awareness of SMART/MART, the strategy appears to be commonly misapplied. Better education for patients and physicians is required to improve asthma management and resulting patient outcomes.

Disease Burden of Patients with Asthma/COPD Overlap in a US Claims Database: Impact of ICD-9 Coding-based Definitions.

The inclusion of an asthma/chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) population in the 2015 Global Initiative for Chronic Obstructive Lung Disease strategic documents has raised questions about the profile of these patients in clinical practice, as they are mostly excluded from asthma and COPD clinical trials. We estimated the disease burden, co-morbidities, and respiratory treatments of patients with asthma/COPD overlap, utilizing the Truven MarketScan commercial and Medicare databases. Patients with ≥1 COPD or chronic obstructive asthma diagnostic code were identified between January 1, 2008, and December 31, 2011. The asthma/COPD overlap group was defined and stratified based upon type and frequency of asthma diagnostic code (chronic obstructive asthma only, COPD and chronic obstructive asthma, and COPD and ≥1 asthma code). 1,488,613 patients were identified; of these, 1,171,626 were diagnosed with COPD alone and 316,987 with asthma/COPD overlap. Patients with asthma and COPD had higher disease burden indicators and inhaled corticosteroid/long-acting beta-agonist use compared with COPD alone. This trend was consistent for all definitions of asthma/COPD overlap. Patients with obstructive asthma and COPD tended to be older, with greater disease burden compared with other definitions; this population may represent a more severe form of asthma/COPD overlap. Disease burden and treatment also varied based on the codes defining asthma/COPD overlap, indicating possible phenotypic differences. More clinical insight and detailed phenotyping is needed to determine the reasons for coding variation in asthma/COPD overlap, with implications for further research to address unmet needs.

Using an electronic medical record (EMR) to conduct clinical trials: Salford Lung Study feasibility.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ß2-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). CONCLUSION: 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.

Respiratory pharmacotherapy use in patients newly diagnosed with chronic obstructive pulmonary disease in a primary care setting in the UK: a retrospective cohort study.

This retrospective cohort study aimed to analyze the prescribing practices of general practitioners treating patients with newly diagnosed chronic obstructive pulmonary disease (COPD), and to assess characteristics associated with initial pharmacotherapy. Patients were identified in the General Practice Research Database, a population-based UK electronic medical record (EMR) with data from January 1, 2008 to December 31, 2009. Patient characteristics, prescribed COPD pharmacotherapies (≤12 months before diagnosis and within 3 months following diagnosis), co-morbidities, hospitalizations, and events indicative of a possible COPD exacerbation (≤12 months before diagnosis) were analyzed in 7881 patients with newly diagnosed COPD. Most patients (64.4%) were prescribed COPD pharmacotherapy in the 12 months before diagnosis. Following diagnosis, COPD pharmacotherapy was prescribed within 3 months in 85.0% of patients. Short-acting bronchodilators alone (22.9%) or inhaled corticosteroids + long-acting beta-2 agonists (ICS+LABA, 22.1%) were prescribed most frequently. Compared with other pharmacotherapies, the prevalence of severe airflow limitation was highest in patients prescribed ICS+LABA+long-acting muscarinic antagonists (LAMA). Moderate-to-severe dyspnea was identified most frequently in patients prescribed a LAMA-containing regimen. Patients prescribed an ICS-containing regimen had a higher prevalence of asthma or possible exacerbations recorded in the EMR than those not prescribed ICS. In conclusion, pharmacotherapy prescribed at initial COPD diagnosis varied by disease severity indicators as assessed by airflow limitation, dyspnea, history of asthma, and possible exacerbations. Frequent prescription of COPD pharmacotherapies before the first-recorded COPD diagnosis indicates a delay between obstructive lung disease presentation in primary care practice and assignment of a medical diagnosis.

Chronic respiratory disease, comorbid cardiovascular disease and mortality in a representative adult US cohort.

BACKGROUND AND OBJECTIVE: We sought to determine the relationship between chronic respiratory disease, cardiovascular disease (CVD) and mortality in a nationally representative cohort of the US population aged 40 years and older. METHODS: We analysed data from the baseline (1988-1994) and follow-up of the Third National Health and Nutrition Examination Survey (NHANES III). Subjects were classified in to one of four categories: obstructed (forced expiratory volume in 1 s/forced vital capacity <70% and forced expiratory volume in 1 s <80% predicted), restricted (forced expiratory volume in 1 s/forced vital capacity ≥70% and forced vital capacity <80% predicted), symptomatic (neither obstructed nor restricted but reporting respiratory symptoms) and normal (none of the above). Subjects were classified as having overt CVD, CVD risk factors only or neither at the baseline examination. RESULTS: The analysis data set included 9054 subjects, of whom 1132 (12.0%, weighted percentage (WP)) were obstructed, 1319 (10.3%, WP) were restricted and 2457 were symptomatic (27.6%, WP). Overt CVD was present at baseline in 1284 subjects (10.4 %, WP), and CVD risk factors alone were present in 4900 (53.3%, WP). Three thousand five hundred seventy-one (28.4%, WP) subjects died during the up to 18-year follow-up period. When compared with 'normal' subjects, those in the obstructed group were more likely to have overt CVD (odds ratio 1.87, 95% confidence interval: 1.15-3.04, P < 0.001), with a similar risk seen in the restricted and symptomatic group. CONCLUSIONS: In this large US population-based cohort, the presence of obstruction, restriction or respiratory symptoms alone was associated with higher adjusted risk of overt CVD.

Lung function impairment, COPD hospitalisations and subsequent mortality.

BACKGROUND: Hospitalisations and their sequelae comprise key morbidities in the natural history of chronic obstructive pulmonary disease (COPD). A study was undertaken to examine the associations between lung function impairment and COPD hospitalisation, and COPD hospitalisation and mortality. METHODS: The analysis included a population-based sample of 20,571 participants with complete demographic, lung function, smoking, hospitalisation and mortality data, with 10-year median follow-up. Participants were classified by prebronchodilator lung function according to the modified Global Initiative on Obstructive Lung Disease (GOLD) criteria. Hospitalisations were defined by the presence of a COPD discharge diagnosis (ICD-9 codes 490-496). Incidence rate ratios (IRR) of COPD admissions and hazard ratios (HR) of mortality with respective 95% CI were calculated, adjusted for potential confounders. RESULTS: The prevalence of modified GOLD categories was normal (36%), restricted (15%), GOLD stage 0 (22%), GOLD stage 1 (13%), GOLD stage 2 (11%) and GOLD stages 3 or 4 (3%). Adjusted IRRs (and 95% CI) indicated an increased risk of COPD hospitalisation associated with each COPD stage relative to normal lung function: 4.7 (3.7 to 6.1), 2.1 (1.6 to 2.6), 3.2 (2.6 to 4.0), 8.0 (6.4 to 10.0) and 25.5 (19.5 to 33.4) for the restricted, GOLD stage 0, GOLD stage 1, GOLD stage 2 and GOLD stages 3 or 4, respectively. Hospitalisation for COPD increased the risk of subsequent mortality (HR 2.7, 95% CI 2.5 to 3.0), controlling for severity, number of prior hospitalisations and other potential confounders. The increase in mortality associated with admission was very similar across the modified GOLD stages. CONCLUSIONS: COPD severity was associated with a higher rate of severe exacerbations requiring hospitalisation, although severe exacerbations at any stage were associated with a higher risk of short-term and long-term all-cause mortality.

Challenges of evaluating and modelling vaccination in emerging infectious diseases.

Outbreaks of emerging pathogens pose unique methodological and practical challenges for the design, implementation, and evaluation of vaccine efficacy trials. Lessons learned from COVID-19 highlight the need for innovative and flexible study design and application to quickly identify promising candidate vaccines. Trial design strategies should be tailored to the dynamics of the specific pathogen, location of the outbreak, and vaccine prototypes, within the regional socioeconomic constraints. Mathematical and statistical models can assist investigators in designing infectious disease clinical trials. We introduce key challenges for planning, evaluating, and modelling vaccine efficacy trials for emerging pathogens.

Long-term use of fluticasone propionate/salmeterol fixed-dose combination and incidence of nonvertebral fractures among patients with COPD in the UK General Practice Research Database.

INTRODUCTION: There has been inconsistent evidence on the association between use of inhaled corticosteroids (ICS) and increased risk of nonvertebral fractures in patients with asthma or chronic obstructive pulmonary disease (COPD). In a large population-based study in the United Kingdom, we estimated the association between fluticasone propionate/salmeterol fixed-dose combination (FSC) and other ICS use and nonvertebral fracture incidence among patients with COPD. METHODS: We identified a cohort of patients aged ≥ 45 years with COPD in the General Practice Research Database (GPRD) between 2003 and 2006. We used a nested case-control design to estimate the odds of incident nonvertebral fractures associated with prior prescriptions of FSC and other ICS, applying conditional logistic regression and controlling for potential confounders. Exposure to FSC and other ICS was assessed by recency, duration, and number of prescriptions. Average daily dose was defined as low, medium, high, or very high using fluticasone propionate equivalents. RESULTS: We identified 1523 nonvertebral fracture cases among 53 191 patients with COPD at risk in the cohort. Use of FSC in the year prior to the index date was associated with a statistically significant increase in the odds of nonvertebral fractures (odds ratio [OR], 1.25; 95% confidence interval [CI], 1.07-1.47); however, there was no increase in the odds of nonvertebral fractures for other ICS use (OR, 1.12; 95% CI, 0.97-1.30). When examining results by the recent use of prescriptions, an exposure that occurred farther from the index date was associated with a significant increase in nonvertebral fracture (26-52 days prior OR, 1.36; 95% CI, 1.04-1.77; 53-365 days prior OR, 1.39; 95% CI, 1.07-1.78), whereas categories of more recent use (0-12 days prior or 13-25 days prior) were not associated with nonvertebral fractures relative to no FSC use. No pattern of association between increasing levels of FSC or other ICS average daily dose and increased odds of nonvertebral fracture was observed. CONCLUSION: We did not observe a consistent association between prescriptions of FSC or other ICS in terms of recent use or average daily dose in the prior year and increases in the odds of nonvertebral fractures in patients with COPD, although ever use of FSC was associated with a slight elevation in the odds.

Masking in Pragmatic Trials: Who, What, and When to Blind.

Masking (or blinding) of treatment assignment is routinely implemented in classical randomized clinical trials (RCTs) to isolate the effect of the intervention itself and to minimize the potential for bias that could occur with traditional trials. Such biases could be introduced with the conduct, assessment of endpoints, management of conditions, analysis, and reporting when the treatment assignments are known. However, masking of treatments is not only complex but it hinders how generalizable the findings are to the "real world" clinical setting. Pragmatic RCTs (pRCTs) are intended to evaluate the effects of interventions within routine medical care, and as such, do not typically mask treatment groups; moreover, pRCTs assess comparators that are available in routine medical practice, not masked placebos. Whether pRCTs should be masked if intended for regulatory or other purposes has recently been questioned. The literature on pRCTs, while extensive, does not address how much actual benefit is gained from masking outcomes and how masking may affect the "real world" nature of a study. Here, we propose an approach to evaluate sources of bias, describe stakeholders in the conduct of pRCTs who are most likely affected, and offer a framework for considering how masking may be implemented effectively while maintaining generalizability.

Study investigating the generalisability of a COPD trial based in primary care (Salford Lung Study) and the presence of a Hawthorne effect.

INTRODUCTION: Traditional phase IIIb randomised trials may not reflect routine clinical practice. The Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) allowed broad inclusion criteria and followed patients in routine practice. We assessed whether SLS COPD approximated the England COPD population and evidence for a Hawthorne effect. METHODS: This observational cohort study compared patients with COPD in the usual care arm of SLS COPD (2012-2014) with matched non-trial patients with COPD in England from the Clinical Practice Research Datalink database. Generalisability was explored with baseline demographics, clinical and treatment variables; outcomes included COPD exacerbations in adjusted models and pretrial versus peritrial comparisons. RESULTS: Trial participants were younger (mean, 66.7 vs 71.1 years), more deprived (most deprived quintile, 51.5% vs 21.4%), more current smokers (47.5% vs 32.1%), with more severe Global initiative for chronic Obstructive Lung Disease stages but less comorbidity than non-trial patients. There were no material differences in other characteristics. Acute COPD exacerbation rates were high in the trial population (98.37th percentile). CONCLUSION: The trial population was similar to the non-trial COPD population. We observed some evidence of a Hawthorne effect, with more exacerbations recorded in trial patients; however, the largest effect was observed through behavioural changes in patients and general practitioner coding practices.

Patterns and management of chronic obstructive pulmonary disease in urban and rural China: a community-based survey of 25 000 adults across 10 regions.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, with COPD deaths in China accounting for one-third of all such deaths. However, there is limited available evidence on the management of COPD in China. METHODS: A random sample of 25 011 participants in the China Kadoorie Biobank, aged 38-87 years, from 10 regions in China was surveyed in 2013-2014. Data were collected using interviewer-administered questionnaires on the diagnosis ('doctor-diagnosed' or 'symptoms-based') and management of COPD (including use of medication and other healthcare resources), awareness of diagnosis and severity of symptoms in COPD cases. RESULTS: Overall, 6.3% of the study population were identified as COPD cases (doctor-diagnosed cases: 4.8% and symptom-based cases: 2.4%). The proportion having COPD was higher in men than in women (7.9% vs 5.3%) and varied by about threefold (3.7%-10.0%) across the 10 regions. Among those with COPD, 54% sought medical advice during the last 12 months, but <10% reported having received treatment for COPD. The rates of hospitalisation for COPD, use of oxygen therapy at home and influenza or pneumococcal vaccinations in the previous year were 15%, 3% and 4%, respectively. Of those with COPD, half had moderate or severe respiratory symptoms, and over 80% had limited understanding of their disease and need for treatment. CONCLUSION: Despite a high prevalence of COPD in China and its substantial impact on activities of daily living, knowledge about COPD and its management were limited.

Excess risk of major vascular diseases associated with airflow obstruction: a 9-year prospective study of 0.5 million Chinese adults.

Background: China has high COPD rates, even among never-regular smokers. Little is known about nonrespiratory disease risks, especially vascular morbidity and mortality after developing airflow obstruction (AFO) in Chinese adults. Objective: We aimed to investigate the prospective association of prevalent AFO with major vascular morbidity and mortality. Materials and methods: In 2004-2008, a nationwide prospective cohort study recruited 512,891 men and women aged 30-79 years from 10 diverse localities across China, tracking cause-specific mortality and coded episodes of hospitalization for 9 years. Cox regression yielded adjusted HRs for vascular diseases comparing individuals with spirometry-defined prevalent AFO at baseline to those without. Results: Of 489,382 participants with no vascular disease at baseline, 6.8% had AFO, with prevalence rising steeply with age. Individuals with prevalent AFO had significantly increased vascular mortality (n=1,429, adjusted HR 1.29, 95% CI 1.21-1.36). There were also increased risks of hemorrhagic stroke (n=823, HR 1.18, 95% CI 1.09-1.27), major coronary events (n=635, HR 1.33, 95% CI 1.22-1.45), and heart failure (n=543, HR 2.19, 95% CI 1.98-2.41). For each outcome, the risk increased progressively with increasing COPD severity and persisted among never-regular smokers. Conclusion: Among adult Chinese, AFO was associated with significantly increased risks of major vascular morbidity and mortality. COPD management should be integrated with vascular disease prevention and treatment programs to improve long-term prognosis.

Asthma and Chronic Obstructive Pulmonary Disease Overlap: The Effect of Definitions on Measures of Burden.

Background: Although the overlap between asthma and COPD has been recognized for years this overlap has only recently been given a name, asthma-COPD overlap syndrome (ACOS), and better defined. Different definitions of the component diseases can affect prevalence and outcome measures of ACOS. Methods: We used data from the National Health and Nutrition Examination Survey (NHANES) from 2007-2012 to determine the population estimates of ACOS in U.S. adults using 2 different definitions of ACOS (ACOS1= self-reported COPD and current asthma; ACOS2 = spirometric-confirmed COPD [pre-bronchodilator FEV1/FVC < 70%] and current asthma) and to describe variation in other factors, such as lung function impairment and health care utilization, by ACOS definitions. Results: Among U.S. adults aged 20 and older, 1.6% had ACOS1, and 1.9% had ACOS2. Both case definitions were similar with regard to symptoms and impairment of lung function. ACOS1 individuals were more likely to have one or more overnight hospital stays relative to those with neither asthma nor COPD, (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.5, 4.6) than ACOS2 (OR 1.6, 95% CI 0.9, 2.9). Conclusions: Different definitions of ACOS in population-based studies affect both estimates of disease prevalence and outcomes related to the disease. These definitions need to be carefully considered in the design of epidemiologic studies and clinical trials.