Skip to main content

Main menu

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • Early View
  • Archive
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • COVID-19 submission information
    • Institutional open access agreements
    • Peer reviewer login
  • Alerts
  • Subscriptions

Observational studies assessing the pharmacological treatment of obstructive lung disease: strengths, challenges and considerations for study design

Jørgen Vestbo, Christer Janson, Javier Nuevo, David Price
ERJ Open Research 2020 6: 00044-2020; DOI: 10.1183/23120541.00044-2020
Jørgen Vestbo
1Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jørgen Vestbo
  • For correspondence: jorgen.vestbo@manchester.ac.uk
Christer Janson
2Dept of Medical Sciences: Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Christer Janson
Javier Nuevo
3AstraZeneca, Evidence Generation, Madrid, Spain
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Price
4Observational and Pragmatic Research Institute, Singapore
5Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for David Price
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Randomised controlled trials (RCTs) are the gold standard for evaluating treatment efficacy in patients with obstructive lung disease. However, due to strict inclusion criteria and the conditions required for ascertaining statistical significance, the patients included typically represent as little as 5% of the general obstructive lung disease population. Thus, studies in broader patient populations are becoming increasingly important. These can be randomised effectiveness trials or observational studies providing data on real-world treatment effectiveness and safety data that complement efficacy RCTs.

In this review we describe the features associated with the diagnosis of asthma and chronic obstructive pulmonary disease (COPD) in the real-world clinical practice setting. We also discuss how RCTs and observational studies have reported opposing outcomes with several treatments and inhaler devices due to differences in study design and the variations in patients recruited by different study types. Whilst observational studies are not without weaknesses, we outline recently developed tools for defining markers of quality of observational studies. We also examine how observational studies are capable of providing valuable insights into disease mechanisms and management and how they are a vital component of research into obstructive lung disease.

As we move into an era of personalised medicine, recent observational studies, such as the NOVEL observational longiTudinal studY (NOVELTY), have the capacity to provide a greater understanding of the value of a personalised healthcare approach in patients in clinical practice by focussing on standardised outcome measures of patient-reported outcomes, physician assessments, airway physiology, and blood and airway biomarkers across both primary and specialist care.

Abstract

Observational studies can support RCTs in influencing clinical practice in the field of obstructive lung disease https://bit.ly/36YWu0W

Introduction

Intervention trials, such as randomised controlled trials (RCTs), and observational studies, such as registry studies have, until recently, been perceived as being distinct and mutually exclusive approaches to clinical research in respiratory medicine, as well as in other fields of medical research. Classical RCTs aim to establish the safety and efficacy of a treatment in the target patient population [1, 2], whereas classical epidemiology observational studies aim to ascertain how often diseases occur in different groups of people and why [3]. Additionally, epidemiological information is used to prepare and evaluate strategies to prevent illness and as a guide for the management of patients in whom disease has already developed [3]. Real-world observational studies with a prospectively recruited cohort aim to establish the effectiveness and safety of a treatment compared with others in a more general population of patients in a real-world, clinical practice setting, both with and without deliberate manipulation or intervention [1]. Furthermore, real-world studies enable exploratory research in broad patient populations that can be used to generate hypotheses, improve understanding of various aspects of disease and treatments, provide novel perspectives and challenge existing paradigms [1, 4].

The aim of this review is to evaluate the strengths and limitations of existing observational studies in assessing the effectiveness of pharmacological treatment in asthma and/or chronic obstructive pulmonary disease (COPD), in order to highlight key considerations for ongoing and future observational studies in obstructive lung disease.

Comparing RCTs with observational real-world studies

Observational studies and classical efficacy RCTs ask distinct research questions and thus employ different study methodologies and patient populations to answer them. Classical efficacy RCTs aim to compare the efficacy and safety of treatments within a patient population selected using strict inclusion criteria (e.g. exclusion of active smokers), with high disease severity (in terms of lung function impairment), good treatment adherence and good inhaler technique, thereby tightly controlling confounding factors. Although this level of internal validity and control makes it easier to identify the absolute benefit or lack of benefit of a treatment, it comes at the cost of external validity [5]; thus, results from efficacy RCTs may not be broadly generalisable to the wider population of patients with obstructive lung disease. Indeed, while RCTs remain the gold standard for evaluating treatments [2], the patients they include can represent as few as 5% of the general asthma/COPD population [6, 7].

In contrast, pragmatic RCTs aim to assess the differential benefit of a treatment in a broader patient population (e.g. patients with less severe lung function impairment and more comorbidities) in a normal ecology of care and with less intensive medical supervision compared with efficacy RCTs [8]. However, pragmatic RCTs still involve a higher organisation of clinical practice than that expected in a real-world setting.

With less intervention and organisation than efficacy RCTs or pragmatic RCTs, pure observational studies offer a more practical and cost-effective means to investigate the long-term outcome of a treatment in a broader patient population than that included in an RCT [5, 8].

As real-world studies differ substantially from efficacy RCTs in their objectives and approach, their study design often requires different considerations and many more patients are eligible for both pragmatic RCTs and observational studies compared with efficacy RCTs [1]. Such studies are seen as increasingly important for understanding treatment effectiveness in a broader patient population [8–11], thereby potentially informing future treatment management strategies.

Real-world studies can take many forms, including the following.

Classical epidemiological studies, e.g. trajectories of lung function in COPD [12], assessing the association between sleep-disordered breathing and asthma [13] management, morbidity and mortality of COPD in Sweden [14] and identifying COPD subtypes and corresponding biomarkers [15].

Retrospective studies using existing, routinely collected health data, such as electronic medical records or insurance claims, e.g. a study on predicting asthma attacks using real-world primary care data in the UK [16].

Post-marketing surveillance/phase IV studies monitor the real-world response to newly approved treatments, including real-world safety and mortality. These studies have helped identify and understand events such as the increased mortality rates observed amongst patients with asthma who received salbutamol (in Australia) and fenoterol (in New Zealand) during the 1980s [17–19].

Comparative effectiveness or safety studies assess the differential benefit of a treatment in broad patient categories to inform a clinical or policy decision by providing evidence for adoption of the intervention into a real-world setting [20, 21]; e.g. The Salford Lung Study (a pragmatic RCT) [9, 10, 22], the Novel START study [23] and the Lung Health Study [24].

In practical terms, real-world studies complement results from RCTs by providing a higher external validity once the efficacy and safety of a treatment has been confirmed under the strictly controlled conditions of an RCT [5, 8]. Tools, such the PRECIS-2, are available to describe the representativeness of a clinical trial compared with a real-world setting and are a valuable resource [25]. In addition, observational studies can be used to investigate aspects that RCTs cannot, such as prevalence and incidence of disease, aetiology, defining prognoses, disease impact, and burden and cost-effectiveness of treatment. Table 1 shows select examples of findings from real-world asthma and COPD data highlighting the different research questions that can be asked from pure observational studies and pragmatic trials covering treatment choice, the use of inhalers, biomarkers and clinical disease history.

View this table:
  • View inline
  • View popup
TABLE 1

Examples of findings from real-world asthma and COPD data highlighting the different research questions that can be asked from pure observational studies and pragmatic trials

Principal causes and factors associated with forced expiratory volume in 1 s decline, COPD and asthma, as established from observational studies

The principal causes and factors associated with forced expiratory volume in 1 s (FEV1) decline, COPD and asthma, as established from previous observational studies, are listed in table 2. Carefully conducted longitudinal studies have been instrumental in establishing causal relationships in obstructive lung disease, with case–control and cohort studies in the 1950s and 1960s firmly establishing cigarette smoking as the single greatest risk factor for lung cancer [48–50]. More recently, ECLIPSE (Evaluation of COPD longitudinally to identify predictive surrogate endpoints), a longitudinal study, was devised with the aim of describing the subtypes of COPD, defining predictive or surrogate markers of disease progression and, potentially, novel targets for therapeutic intervention [15].

View this table:
  • View inline
  • View popup
TABLE 2

The principal causes and factors associated with FEV1 decline, COPD and asthma, as established from observational studies

Despite having plateaued and even fallen in some regions, globally the prevalence of asthma has been increasing rapidly for several decades [51]. There is a strong genetic component in asthma, demonstrated by concordance of approximately 50% in monozygotic twins with asthma [52]; however, the speed of the increase in prevalence is thought to be too high to be accounted for by a genetic change alone and is therefore more likely to be related to environmental changes [53].

Comparing guidelines, RCTs and observational study outcomes in obstructive lung disease

Treatment options

Results from RCTs have indicated a benefit of adding low-dose oral theophylline to inhaled corticosteroid (ICS) therapy for COPD [94, 95]; however, UK National Institute for Health and Care Excellence (NICE) guidelines for COPD do not recommend theophylline as the first-choice of treatment [96], and the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) report states that there is only limited and contradictory evidence for the use of low-dose theophylline [97]. In addition, results from the TWICS (theophylline with inhaled corticosteroids) pragmatic trial found no benefit of theophylline added to ICS over placebo in a real-world setting [46]. Similarly, a systematic review of RCTs for asthma demonstrated the superiority of ICS over leukotriene receptor antagonists (LTRA) for the management of asthma [98]; however, the ELEVATE (A pragmatic randomised single-blind 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) pragmatic study found no difference in effectiveness between ICS and LTRA [45]. These seemingly conflicting findings may be due, in part, to the different patient populations included and the lower adherence rate with ICS versus LTRA [45, 99].

In terms of treatment reduction, the Global Initiative for Asthma (GINA) recommends stepping down ICS/long-acting β2-agonist (LABA) dose once asthma control has been achieved for ≥3 months [100]. However, the FFLUX (A randomised pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma) pragmatic trial that investigated the stepping-down of treatment in patients who were stable following 12 weeks of treatment, found that patients with a history of one or two exacerbations within 12 months prior to starting treatment were at increased risk of re-exacerbation [44]. This highlights the need for research beyond the outcomes of efficacy RCTs to be considered when guidelines are developed and in this specific case, the need for asthma exacerbation history to be considered in guiding clinicians in stepping-down of treatment.

Until relatively recently, the recommended treatment for asthma has been ICS maintenance treatment with as-needed short-acting β2-agonists (SABAs) [101]. However, real-world data have found that patients typically underuse ICS and overuse SABA [102]. This has led to the observation that overuse of SABA is associated with an increase in all-cause mortality risk in patients with asthma [103]; the subsequent revision of the guidelines to recommend combined ICS/SABA as needed demonstrates how the outcomes of observational studies are influencing global guidelines [100].

Real-world data may also provide complementary evidence to support findings from RCTs. The Salford Lung Study pragmatic trial successfully demonstrated the real-world effectiveness of fluticasone furoate/vilanterol treatment for maintenance therapy of COPD [10] and asthma [9], adding to the findings from previous RCTs.

Some studies have also suggested limited value or even harm of certain therapies in COPD. An observational nested case–control study of patients with COPD being treated with LABA and ICS from registry data over 4.5 years found that the addition of the long-acting muscarinic antagonist (LAMA) tiotropium was associated with an increased cardiovascular risk in patients with COPD [104]. However, none of the recent fixed triple combination registration trials have seen this effect and in the three-year ASCENT (Evaluate the effect of aclidinium bromide on long-term cardiovascular safety and exacerbations in moderate to very severe COPD patients) RCT of patients with COPD and high cardiovascular risk, there was no increase in the risk of cardiovascular events for patients receiving the LAMA aclidinium compared with placebo [105].

Inhaler device, technique and adherence

RCTs typically ensure that patients demonstrate correct inhaler technique and adhere to their treatment; thus, results from RCTs reflect the efficacy of inhalers under a near-perfect technique and adherence rate [106, 107]. However, inhalation errors in a real-world setting have been shown to increase the risk of poor treatment outcomes, such as hospitalisation, medication use and symptom control [35, 36, 107]. In addition, mixing inhaler devices may lead to worse COPD outcomes than when single devices or devices requiring the same inhalation technique are used [29, 30]. Thus, results from real-world studies emphasise the importance of ensuring proper inhaler technique to maximise treatment success in both asthma and COPD. Other examples of findings from real-world evidence in asthma/COPD can be found in table 1.

With regard to specific inhaler types, according to the recommendations of the British Thoracic Society Scottish Intercollegiate Guidelines Network [108] and results from interventional RCTs, dry powder inhalers (DPI) are as effective as pressurised metered-dose inhalers (pMDI) for the delivery of ICS treatment [109, 110]. This is supported by a recent study utilising the Korean Health Insurance Claims database, which found a comparable clinical and cost efficiency between patients with asthma who switched from a DPI to a pMDI versus patients who remained on a DPI [28]. However, other results have been more conflicting [35, 36, 106, 107, 111] and real-world studies from the UK have suggested that pMDIs are superior to DPIs in both asthma [31] and COPD [32], illustrating that the outcomes of observational studies can still be conflicting and the importance of understanding the different methodologies and analyses used.

Weaknesses of observational studies

It is important to note that despite the many advantages of observational studies, as with all study designs, the methodologies employed are subject to specific biases, including selection bias (systematic differences between baseline characteristics of the groups that are compared) and detection bias (systematic differences between groups in how outcomes are determined) [112]. Studies utilising electronic health records are further susceptible to a degree of inaccuracy and incompleteness; such records are typically collected for routine medical purposes and can lack the quality, detail and accuracy typically required for research purposes [113].

In enrolling a broad patient population, the analysis of data generated from observational studies is complicated by confounding factors such as confounding by indication; i.e. most patients receiving medication in an observational study have been formerly diagnosed by a doctor whereas those without the medication have not, despite otherwise appearing almost identical [114]. Another factor which must be considered is the avoidance of immortal time balance, which can be the consequence of incorrect handling of the period between study entry and treatment initiation in time-to-event analyses [115]. For time-dependent confounders, such as body mass index, which is a risk factor for asthma that may lead to reduced physical activity and is also affected by prior levels of physical activity, the parametric g-formula can be used in place of conventional regression approaches [116, 117].

Biases in observational studies can be significantly reduced by using a prospective study design and a predefined statistical analysis plan [5, 118]. In addition, tools such as the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) [119] and Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies [120] may also be beneficial in minimising bias. However, while statistical adjustment and matching can be used to minimise confounding effects [5, 118], factors which are not accounted for, and thus not recorded within the study, are likely to remain. It should be noted that RCTs are often also affected by bias, such as selection and information bias, although this is not always recognised.

Markers of quality for observational studies

Despite their shortcomings, clinical guidelines still place a greater emphasis on results from classical RCTs than from observational studies [8]. Indeed, traditional tools for rating quality of studies such as the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) also downgrade observational study designs [8].

To achieve greater integration of real-world evidence into the development programmes of new drugs, it is vital that observational studies are subjected to standards that are as equally rigorous as those devised for classical RCTs [8]. There is, therefore, a need to standardise the quality of real-world evidence. Recently, a joint task force between the Respiratory Effectiveness Group and the European Academy of Allergy and Clinical Immunology (EAACI) developed a standardised tool for quality appraisal of comparative effectiveness studies, the REal Life EVidence AssessmeNt Tool (RELEVANT; www.regresearchnetwork.org/relevant-tool-2) [121]. The tool incorporates 21 quality checklist items, of which 11 primary items determine a study's suitability for guideline development and 10 secondary items are for general appraisal of the study. Quality appraisal using the RELEVANT tool on selected examples of comparative effectiveness studies are presented in table 3; similar tools are already available for evaluating observational studies [122, 123].

View this table:
  • View inline
  • View popup
TABLE 3

Author's appraisal of selected comparative effectiveness studies using RELEVANT 2.0 tool [121]

Why we need both RCTs and observational studies

Comparing RCT and observational study data by adjusting and aligning patient data has further highlighted the importance of using both study types to assess the effect of a treatment. A number of studies on the use of statins in patients with COPD have indicated that statins may provide additional benefits in terms of improving lung function and reducing risk of exacerbation, hospitalisation and death [124–126], potentially through reduction of inflammation [127]. Of particular interest, the STATCOPE (Simvastatin for the prevention of exacerbations in moderate-to-severe COPD) RCT found that statins had no impact on exacerbation risk, lung function, or on general or disease-specific quality of life in patients with COPD [128]. In contrast, an observational study by Ingebrigtsen et al. [129] found that statins did reduce exacerbation risk. However, when these same observational data were adjusted to align the patients with those from the STATCOPE RCT, statins were found to provide no additional benefit in patients with COPD. Due to the inherent differences in the patient populations of RCTs and observational studies, as previously described, this finding clearly demonstrates why both RCTs and observational studies are needed to form a complete picture of treatment effect.

Future prospects in real-world evidence in asthma/COPD

Several complex observational studies in asthma/COPD have contributed to a greater understanding of the heterogeneity of the asthma/COPD population in a real-world setting, including COPDGene [130], ECLIPSE [15], SPIROMICS (Subpopulations and intermediary outcomes in COPD study; U-BIOPRED: Unbiased biomarkers in prediction of respiratory disease outcomes) [131] and U-BIOPRED [132]. These studies have led to an increasing recognition of the importance of personalised healthcare and the value of endotype-driven assessment and management [133]. However, to date, both RCTs and real-world studies have largely examined the effects of pharmacological treatment at a population level. Thus, although treatment has been shown to have a statistically significant impact on symptoms, exacerbations and airflow obstruction, the scale of the effects at the group level are often limited, suggesting that not all patients may gain the same effect from treatment. Thus, as we enter an era of personalised medicine, there is a need to identify the individual patient factors that are associated with treatment response.

The recent shift towards a treatment approach guided by treatable disease characteristics, or traits [134], that is less dependent on conventional diagnostic labels, has highlighted a lack of studies that span both COPD and asthma across a broad range of severities. In order to provide a greater understanding of the value of a personalised healthcare approach in patients in clinical practice, there is a need for large-scale, inclusive observational studies with standardised outcome measures and a focus on patient-reported outcomes, physician assessments, airway physiology and blood and airway biomarkers across both primary and specialist care. The NOVEL observational longiTudinal studY (NOVELTY) study (NCT02760329) is one such study that aims to address this need [135]. NOVELTY is a global (19 countries), 3-year prospective, observational study of >12 000 patients with a diagnosis or suspected diagnosis of asthma and/or COPD that aims to describe patient characteristics, treatment patterns and burden of illness, and to identify the clinical phenotypes and molecular endotypes (based on biomarkers and/or clinical parameters) that are associated with differential outcomes for symptom burden, clinical evolution and healthcare utilisation over time. It is expected that the majority of patients enrolled in NOVELTY would not have been eligible for inclusion in most RCTs, therefore NOVELTY offers the prospect of investigating disease mechanisms and outcomes in a more clinically relevant population than that provided by a classical RCT.

Conclusions

Real-world evidence is capable of providing valuable insights into disease mechanisms and management; however, due to the potential for producing large amounts of data and analyses compared with RCTs, it is vital that they are designed with clear research questions in mind. These research questions may demand different methodologies and, as such, will guide the type of study that is required. This will help to challenge perceptions that real-world evidence is solely for the evaluation of safety/epidemiology, and will demonstrate that they can also inform on patient outcomes if designed with clear research questions. Furthermore, due to the inclusion of a broader range of patients than RCTs, real-world studies require a much greater understanding of confounders and modifiers of effects compared with RCTs to aid interpretation of their findings.

Observational real-world studies are a vital component of research into obstructive lung disease, and well-designed observational studies can support pivotal RCTs and provide evidence that has the potential to influence clinical practice. Although observational studies are subject to specific challenges, with the aid of recently developed quality standard tools, these challenges can be factored into study design to produce high-quality results. In future, well-designed, real-world studies that include a broad range of patients (in terms of geographical location, care setting and severity level) across both asthma and COPD diagnoses will be instrumental in supporting a more personalised, endotype-driven approach to the assessment and management of patients with obstructive lung disease.

Acknowledgements

Editorial support under the direction of the authors was provided by Richard Knight, CMC Connect, McCann Health Medical Communications, and funded by AstraZeneca in accordance with Good Publication Practice guidelines. The first draft of the manuscript was written in three sections by J. Vestbo, C. Janson and D. Price. Editorial support specifically for D. Price was provided by Antony Hardjojo of the Observational and Pragmatic Research Institute, Singapore. J. Vestbo is supported by the NIHR Manchester BRC.

Footnotes

  • Conflict of interest: J. Vestbo reports personal fees from AstraZeneca for co-chairing the NOVELTY study, from which the idea for this article arose, during the conduct of the study; honoraria for presenting and/or advising on COPD from AstraZeneca, an unconditional biomarker grant and honoraria for presenting and/or advising on COPD from Boehringer Ingelheim, honoraria for presenting and/or advising on COPD from Chiesi, an honorarium for advising on COPD from GSK, and honoraria for presenting and/or advising on COPD fees from Novartis, outside the submitted work; and his son is an employee of Chiesi (Denmark).

  • Conflict of interest: C. Janson has nothing to disclose.

  • Conflict of interest: J. Nuevo is an employee of AstraZeneca.

  • Conflict of interest: D. Price reports grants from AKL Research and Development Ltd, personal fees from Amgen, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants from British Lung Foundation, grants and personal fees from Chiesi, grants and personal fees from Circassia, personal fees from Cipla, personal fees from GlaxoSmithKline, personal fees from Kyorin, personal fees from Merck, grants and personal fees from Mylan, grants and personal fees from Mundipharma, grants and personal fees from Napp, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Regeneron Pharmaceuticals, grants from Respiratory Effectiveness Group, grants and personal fees from Sanofi Genzyme, grants and personal fees from Teva, grants and personal fees from Theravance, grants from UK National Health Service, grants and personal fees from Zentiva (Sanofi Generics), non-financial support from Efficacy and Mechanism Evaluation programme, non-financial support from Health Technology Assessment, outside the submitted work; stock/stock options from AKL Research and Development Ltd, which produces phytopharmaceuticals; and owns 74% of the social enterprise Optimum Patient Care Ltd (Australia and UK) and 74% of Observational and Pragmatic Research Institute Pte Ltd (Singapore).

  • Support statement: The development of this manuscript was funded by AstraZeneca. Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received January 28, 2020.
  • Accepted June 1, 2020.
  • Copyright ©ERS 2020
http://creativecommons.org/licenses/by-nc/4.0/

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

References

  1. ↵
    1. Saturni S,
    2. Bellini F,
    3. Braido F, et al.
    Randomized controlled trials and real life studies. Approaches and methodologies: a clinical point of view. Pulm Pharmacol Ther 2014; 27: 129–138. doi:10.1016/j.pupt.2014.01.005
    OpenUrlCrossRefPubMed
  2. ↵
    1. Nallamothu BK,
    2. Hayward RA,
    3. Bates ER
    . Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular therapies. Circulation 2008; 118: 1294–1303. doi:10.1161/CIRCULATIONAHA.107.703579
    OpenUrlFREE Full Text
  3. ↵
    1. Coggon D,
    2. Rose G,
    3. Barker DJP
    . Epidemiology for the uninitiated. www.bmj.com/about-bmj/resources-readers/publications/epidemiology-uninitiated Date last accessed: September 5, 2019; date last updated: August 11, 2020.
  4. ↵
    1. Price D,
    2. Chisholm A,
    3. van der Molen T, et al.
    Reassessing the evidence hierarchy in asthma: evaluating comparative effectiveness. Curr Allergy Asthma Rep 2011; 11: 526–538. doi:10.1007/s11882-011-0222-7
    OpenUrlCrossRefPubMed
  5. ↵
    1. Price D,
    2. Bateman ED,
    3. Chisholm A, et al.
    Complementing the randomized controlled trial evidence base. Evolution not revolution. Ann Am Thorac Soc 2014; 11: Suppl. 2, S92–S98. doi:10.1513/AnnalsATS.201308-276RM
    OpenUrlCrossRefPubMed
  6. ↵
    1. Herland K,
    2. Akselsen JP,
    3. Skjønsberg OH, et al.
    How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir Med 2005; 99: 11–19. doi:10.1016/j.rmed.2004.03.026
    OpenUrlCrossRefPubMed
  7. ↵
    1. Travers J,
    2. Marsh S,
    3. Williams M, et al.
    External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007; 62: 219–223. doi:10.1136/thx.2006.066837
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Price D,
    2. Brusselle G,
    3. Roche N, et al.
    Real-world research and its importance in respiratory medicine. Breathe 2015; 11: 26–38. doi:10.1183/20734735.015414
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Woodcock A,
    2. Boucot I,
    3. Leather DA, et al.
    Effectiveness versus efficacy trials in COPD: how study design influences outcomes and applicability. Eur Respir J 2018; 51: 1701531. doi:10.1183/13993003.01531-2017
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Vestbo J,
    2. Leather D,
    3. Diar Bakerly N, et al.
    Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med 2016; 375: 1253–1260. doi:10.1056/NEJMoa1608033
    OpenUrl
  11. ↵
    1. Barrecheguren M,
    2. González C,
    3. Miravitlles M
    . What have we learned from observational studies and clinical trials of mild to moderate COPD? Respir Res 2018; 19: 177. doi:10.1186/s12931-018-0882-0
    OpenUrl
  12. ↵
    1. Lange P,
    2. Celli B,
    3. Agustí A, et al.
    Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med 2015; 373: 111–122. doi:10.1056/NEJMoa1411532
    OpenUrlCrossRefPubMed
  13. ↵
    1. Li L,
    2. Xu Z,
    3. Jin X, et al.
    Sleep-disordered breathing and asthma: evidence from a large multicentric epidemiological study in China. Respir Res 2015; 16: 56. doi:10.1186/s12931-015-0215-5
    OpenUrl
  14. ↵
    1. Ställberg B,
    2. Janson C,
    3. Johansson G, et al.
    Management, morbidity and mortality of COPD during an 11-year period: an observational retrospective epidemiological register study in Sweden (PATHOS). Prim Care Respir J 2014; 23: 38–45. doi:10.4104/pcrj.2013.00106
    OpenUrlPubMed
  15. ↵
    1. Vestbo J,
    2. Anderson W,
    3. Coxson HO, et al.
    Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 2008; 31: 869–873. doi:10.1183/09031936.00111707
    OpenUrlAbstract/FREE Full Text
  16. ↵
    1. Turner SW,
    2. Murray C,
    3. Thomas M, et al.
    Applying UK real-world primary care data to predict asthma attacks in 3776 well-characterised children: a retrospective cohort study. NPJ Prim Care Respir Med 2018; 28: 28. doi:10.1038/s41533-018-0095-5
    OpenUrl
  17. ↵
    1. Beasley R
    . A historical perspective of the New Zealand asthma mortality epidemics. J Allergy Clin Immunol 2006; 117: 225–228. doi:10.1016/j.jaci.2005.10.029
    OpenUrlCrossRefPubMed
    1. Ebmeier S,
    2. Thayabaran D,
    3. Braithwaite I, et al.
    Trends in international asthma mortality: analysis of data from the WHO Mortality Database from 46 countries (1993–2012). Lancet 2017; 390: 935–945. doi:10.1016/S0140-6736(17)31448-4
    OpenUrlCrossRefPubMed
  18. ↵
    1. Abramson MJ,
    2. Bailey MJ,
    3. Couper FJ, et al.
    Are asthma medications and management related to deaths from asthma? Am J Respir Crit Care Med 2001; 163: 12–18. doi:10.1164/ajrccm.163.1.9910042
    OpenUrlCrossRefPubMed
  19. ↵
    1. Ford I,
    2. Norrie J
    . Pragmatic Trials. N Engl J Med 2016; 375: 454–463. doi:10.1056/NEJMra1510059
    OpenUrlCrossRefPubMed
  20. ↵
    1. Schwartz D,
    2. Lellouch J
    . Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967; 20: 637–648. doi:10.1016/0021-9681(67)90041-0
    OpenUrlCrossRefPubMed
  21. ↵
    1. Albertson TE,
    2. Murin S,
    3. Sutter ME, et al.
    The Salford Lung Study: a pioneering comparative effectiveness approach to COPD and asthma in clinical trials. Pragmat Obs Res 2017; 8: 175–181. doi:10.2147/POR.S144157
    OpenUrl
  22. ↵
    1. Beasley R,
    2. Holliday M,
    3. Reddel HK, et al.
    Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med 2019; 380: 2020–2030. doi:10.1056/NEJMoa1901963
    OpenUrlPubMed
  23. ↵
    1. Anthonisen NR,
    2. Connett JE,
    3. Kiley JP, et al.
    Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994; 272: 1497–1505. doi:10.1001/jama.1994.03520190043033
    OpenUrlCrossRefPubMed
  24. ↵
    1. Loudon K,
    2. Treweek S,
    3. Sullivan F, et al.
    The PRECIS-2 tool: designing trials that are fit for purpose. BMJ 2015; 350: h2147. doi:10.1136/bmj.h2147
    OpenUrlFREE Full Text
    1. Buhl R,
    2. Criée CP,
    3. Kardos P, et al.
    Dual bronchodilation vs triple therapy in the “real-life” COPD DACCORD study. Int J Chron Obstruct Pulmon Dis 2018; 13: 2557–2568. doi:10.2147/COPD.S169958
    OpenUrlPubMed
    1. Kardos P,
    2. Mokros I,
    3. Sauer R, et al.
    Health status in patients with COPD treated with roflumilast: two large noninterventional real-life studies: DINO and DACOTA. Int J Chron Obstruct Pulmon Dis 2018; 13: 1455–1468. doi:10.2147/COPD.S159827
    OpenUrl
  25. ↵
    1. Rhee CK,
    2. van Boven JFM,
    3. Yau Ming SW, et al.
    Does changing inhaler device impact real-life asthma outcomes? Clinical and economic evaluation. J Allergy Clin Immunol Pract 2019; 7: 934–942. doi:10.1016/j.jaip.2018.09.027
    OpenUrl
  26. ↵
    1. Bosnic-Anticevich S,
    2. Chrystyn H,
    3. Costello RW, et al.
    The use of multiple respiratory inhalers requiring different inhalation techniques has an adverse effect on COPD outcomes. Int J Chron Obstruct Pulmon Dis 2017; 12: 59–71. doi:10.2147/COPD.S117196
    OpenUrl
  27. ↵
    1. Price D,
    2. Chrystyn H,
    3. Kaplan A, et al.
    Effectiveness of same versus mixed asthma inhaler devices: a retrospective observational study in primary care. Allergy Asthma Immunol Res 2012; 4: 184–191. doi:10.4168/aair.2012.4.4.184
    OpenUrlPubMed
  28. ↵
    1. Price D,
    2. Roche N,
    3. Christian Virchow J, et al.
    Device type and real-world effectiveness of asthma combination therapy: an observational study. Respir Med 2011; 105: 1457–1466. doi:10.1016/j.rmed.2011.04.010
    OpenUrlPubMed
  29. ↵
    1. Jones R,
    2. Martin J,
    3. Thomas V, et al.
    The comparative effectiveness of initiating fluticasone/salmeterol combination therapy via pMDI versus DPI in reducing exacerbations and treatment escalation in COPD: a UK database study. Int J Chron Obstruct Pulmon Dis 2017; 12: 2445–2454. doi:10.2147/COPD.S141409
    OpenUrl
    1. Sulaiman I,
    2. Seheult J,
    3. MacHale E, et al.
    Irregular and ineffective: A quantitative observational study of the time and technique of inhaler use. J Allergy Clin Immunol Pract 2016; 4: 900–909 e902. doi:10.1016/j.jaip.2016.07.009
    OpenUrl
    1. Ocakli B,
    2. Ozmen I,
    3. Tunçay EA, et al.
    A comparative analysis of errors in inhaler technique among COPD versus asthma patients. Int J Chron Obstruct Pulmon Dis 2018; 13: 2941–2947. doi:10.2147/COPD.S178951
    OpenUrl
  30. ↵
    1. Melani AS,
    2. Bonavia M,
    3. Cilenti V, et al.
    Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med 2011; 105: 930–938. doi:10.1016/j.rmed.2011.01.005
    OpenUrlCrossRefPubMed
  31. ↵
    1. Price DB,
    2. Román-Rodríguez M,
    3. McQueen RB, et al.
    Inhaler errors in the CRITIKAL study: Type, frequency, and association with asthma outcomes. J Allergy Clin Immunol Pract 2017; 5: 1071–1081. doi:10.1016/j.jaip.2017.01.004
    OpenUrl
    1. Zeiger RS,
    2. Schatz M,
    3. Li Q, et al.
    High blood eosinophil count is a risk factor for future asthma exacerbations in adult persistent asthma. J Allergy Clin Immunol Pract 2014; 2: 741–750. doi:10.1016/j.jaip.2014.06.005
    OpenUrl
    1. Zeiger RS,
    2. Schatz M,
    3. Yang SJ, et al.
    Fractional exhaled nitric oxide-assisted management of uncontrolled persistent asthma: A real-world prospective observational study. Perm J 2019; 23: 18–109.
    OpenUrlCrossRefPubMed
    1. Kerkhof M,
    2. Sonnappa S,
    3. Postma DS, et al.
    Blood eosinophil count and exacerbation risk in patients with COPD. Eur Respir J 2017; 50: 1700761. doi:10.1183/13993003.00761-2017
    OpenUrlAbstract/FREE Full Text
    1. Price DB,
    2. Rigazio A,
    3. Campbell JD, et al.
    Blood eosinophil count and prospective annual asthma disease burden: a UK cohort study. Lancet Respir Med 2015; 3: 849–858. doi:10.1016/S2213-2600(15)00367-7
    OpenUrl
    1. Jones RC,
    2. Price D,
    3. Ryan D, et al.
    Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med 2014; 2: 267–276. doi:10.1016/S2213-2600(14)70008-6
    OpenUrl
    1. Veenendaal M,
    2. Westerik JAM,
    3. van den Bemt L, et al.
    Age- and sex-specific prevalence of chronic comorbidity in adult patients with asthma: A real-life study. NPJ Prim Care Respir Med 2019; 29: 14. doi:10.1038/s41533-019-0127-9
    OpenUrl
    1. Wang E,
    2. Wechsler ME,
    3. Tran TN, et al.
    Characterization of severe asthma worldwide: data from the International Severe Asthma Registry (ISAR). Chest 2020; 157: 790–804.
    OpenUrl
  32. ↵
    1. Usmani OS,
    2. Kemppinen A,
    3. Gardener E, et al.
    A randomized pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma. J Allergy Clin Immunol Pract 2017; 5: 1378–1387.e1375. doi:10.1016/j.jaip.2017.02.006
    OpenUrl
  33. ↵
    1. Price D,
    2. Musgrave SD,
    3. Shepstone L, et al.
    Leukotriene antagonists as first-line or add-on asthma-controller therapy. N Engl J Med 2011; 364: 1695–1707. doi:10.1056/NEJMoa1010846
    OpenUrlCrossRefPubMed
  34. ↵
    1. Devereux G,
    2. Cotton S,
    3. Fielding S, et al.
    Effect of theophylline as adjunct to inhaled corticosteroids on exacerbations in patients with COPD: A randomized clinical trial. JAMA 2018; 320: 1548–1559. doi:10.1001/jama.2018.14432
    OpenUrl
    1. Price DB,
    2. Buhl R,
    3. Chan A, et al.
    Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2018; 6: 29–39. doi:10.1016/S2213-2600(17)30424-1
    OpenUrl
  35. ↵
    1. Samet JM
    . The epidemiology of lung cancer. Chest 1993; 103: 20S–29S. doi:10.1378/chest.103.1_Supplement.20S
    OpenUrlPubMed
    1. Doll R,
    2. Hill AB
    . Smoking and carcinoma of the lung; preliminary report. Br Med J 1950; 2: 739–748. doi:10.1136/bmj.2.4682.739
    OpenUrlFREE Full Text
  36. ↵
    US Public Health Service. Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service. Washington, U.S. Public Health Service, 1964.
  37. ↵
    1. Eder W,
    2. Ege MJ,
    3. von Mutius E
    . The asthma epidemic. N Engl J Med 2006; 355: 2226–2235. doi:10.1056/NEJMra054308
    OpenUrlCrossRefPubMed
  38. ↵
    1. Kuruvilla ME,
    2. Vanijcharoenkarn K,
    3. Shih JA, et al.
    Epidemiology and risk factors for asthma. Respir Med 2019; 149: 16–22. doi:10.1016/j.rmed.2019.01.014
    OpenUrl
  39. ↵
    1. Burbank AJ,
    2. Sood AK,
    3. Kesic MJ, et al.
    Environmental determinants of allergy and asthma in early life. J Allergy Clin Immunol 2017; 140: 1–12. doi:10.1016/j.jaci.2017.05.010
    OpenUrl
    1. Lundbäck B,
    2. Lindberg A,
    3. Lindström M, et al.
    Not 15 but 50% of smokers develop COPD? Report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med 2003; 97: 115–122. doi:10.1053/rmed.2003.1446
    OpenUrlCrossRefPubMed
    1. Perret JL,
    2. Walters H,
    3. Johns D, et al.
    Mother's smoking and complex lung function of offspring in middle age: A cohort study from childhood. Respirology 2016; 21: 911–919. doi:10.1111/resp.12750
    OpenUrlCrossRefPubMed
    1. Hanrahan JP,
    2. Tager IB,
    3. Segal MR, et al.
    The effect of maternal smoking during pregnancy on early infant lung function. Am Rev Respir Dis 1992; 145: 1129–1135. doi:10.1164/ajrccm/145.5.1129
    OpenUrlCrossRefPubMed
    1. Tager IB,
    2. Ngo L,
    3. Hanrahan JP
    . Maternal smoking during pregnancy. Effects on lung function during the first 18 months of life. Am J Respir Crit Care Med 1995; 152: 977–983. doi:10.1164/ajrccm.152.3.7663813
    OpenUrlCrossRefPubMed
    1. Schell LM,
    2. Hodges DC
    . Variation in size at birth and cigarette smoking during pregnancy. Am J Phys Anthropol 1985; 68: 549–554. doi:10.1002/ajpa.1330680411
    OpenUrlCrossRefPubMed
    1. Gold DR,
    2. Wang X,
    3. Wypij D, et al.
    Effects of cigarette smoking on lung function in adolescent boys and girls. N Engl J Med 1996; 335: 931–937. doi:10.1056/NEJM199609263351304
    OpenUrlCrossRefPubMed
    1. Heederik D,
    2. Kromhout H,
    3. Kromhout D, et al.
    Relations between occupation, smoking, lung function, and incidence and mortality of chronic non-specific lung disease: the Zutphen Study. Br J Ind Med 1992; 49: 299–308.
    OpenUrlPubMed
    1. Bergdahl IA,
    2. Torén K,
    3. Eriksson K, et al.
    Increased mortality in COPD among construction workers exposed to inorganic dust. Eur Respir J 2004; 23: 402–406. doi:10.1183/09031936.04.00034304
    OpenUrlAbstract/FREE Full Text
    1. Kauffmann F,
    2. Drouet D,
    3. Lellouch J, et al.
    Occupational exposure and 12-year spirometric changes among Paris area workers. Br J Ind Med 1982; 39: 221–232.
    OpenUrlPubMed
    1. Humerfelt S,
    2. Gulsvik A,
    3. Skjærven R, et al.
    Decline in FEV1 and airflow limitation related to occupational exposures in men of an urban community. Eur Respir J 1993; 6: 1095–1103.
    OpenUrlAbstract/FREE Full Text
    1. Po JY,
    2. FitzGerald JM,
    3. Carlsten C
    . Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. Thorax 2011; 66: 232–239. doi:10.1136/thx.2010.147884
    OpenUrlAbstract/FREE Full Text
    1. Balcan B,
    2. Akan S,
    3. Ugurlu AO, et al.
    Effects of biomass smoke on pulmonary functions: a case control study. Int J Chron Obstruct Pulmon Dis 2016; 11: 1615–1622. doi:10.2147/COPD.S109056
    OpenUrl
    1. Ramírez-Venegas A,
    2. Sansores RH,
    3. Quintana-Carrillo RH, et al.
    FEV1 decline in patients with chronic obstructive pulmonary disease associated with biomass exposure. Am J Respir Crit Care Med 2014; 190: 996–1002. doi:10.1164/rccm.201404-0720OC
    OpenUrlCrossRefPubMed
    1. Burney P,
    2. Jithoo A,
    3. Kato B, et al.
    Chronic obstructive pulmonary disease mortality and prevalence: the associations with smoking and poverty--a BOLD analysis. Thorax 2014; 69: 465–473. doi:10.1136/thoraxjnl-2013-204460
    OpenUrlAbstract/FREE Full Text
    1. Prescott E,
    2. Vestbo J
    . Socioeconomic status and chronic obstructive pulmonary disease. Thorax 1999; 54: 737–741. doi:10.1136/thx.54.8.737
    OpenUrlFREE Full Text
    1. Huisman M,
    2. Kunst AE,
    3. Bopp M, et al.
    Educational inequalities in cause-specific mortality in middle-aged and older men and women in eight western European populations. Lancet 2005; 365: 493–500. doi:10.1016/S0140-6736(05)17867-2
    OpenUrlCrossRefPubMed
    1. Smith GD,
    2. Hart C,
    3. Blane D, et al.
    Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study. BMJ 1998; 316: 1631–1635. doi:10.1136/bmj.316.7145.1631
    OpenUrlAbstract/FREE Full Text
    1. Vestbo J,
    2. Prescott E,
    3. Lange P
    . Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity. Copenhagen City Heart Study Group. Am J Respir Crit Care Med 1996; 153: 1530–1535. doi:10.1164/ajrccm.153.5.8630597
    OpenUrlCrossRefPubMed
    1. Lange P,
    2. Nyboe J,
    3. Appleyard M, et al.
    Relation of ventilatory impairment and of chronic mucus hypersecretion to mortality from obstructive lung disease and from all causes. Thorax 1990; 45: 579–585. doi:10.1136/thx.45.8.579
    OpenUrlAbstract/FREE Full Text
    1. Prescott E,
    2. Lange P,
    3. Vestbo J
    . Chronic mucus hypersecretion in COPD and death from pulmonary infection. Eur Respir J 1995; 8: 1333–1338. doi:10.1183/09031936.95.08081333
    OpenUrlAbstract
    1. Guerra S,
    2. Sherrill DL,
    3. Venker C, et al.
    Chronic bronchitis before age 50 years predicts incident airflow limitation and mortality risk. Thorax 2009; 64: 894–900. doi:10.1136/thx.2008.110619
    OpenUrlAbstract/FREE Full Text
    1. Marcon A,
    2. Locatelli F,
    3. Keidel D, et al.
    Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study. Thorax 2018; 73: 825–832. doi:10.1136/thoraxjnl-2017-211289
    OpenUrlAbstract/FREE Full Text
    1. Vestbo J,
    2. Prescott E
    . Update on the ‘Dutch hypothesis’ for chronic respiratory disease. Thorax 1998; 53: Suppl. 2, S15–S19. doi:10.1136/thx.53.2008.S15
    OpenUrlAbstract
    1. Rogliani P,
    2. Ora J,
    3. Puxeddu E, et al.
    Airflow obstruction: is it asthma or is it COPD? Int J Chron Obstruct Pulmon Dis 2016; 11: 3007–3013. doi:10.2147/COPD.S54927
    OpenUrl
    1. Tovey ER,
    2. Almqvist C,
    3. Li Q, et al.
    Nonlinear relationship of mite allergen exposure to mite sensitization and asthma in a birth cohort. J Allergy Clin Immunol 2008; 122: 114–118. doi:10.1016/j.jaci.2008.05.010
    OpenUrlCrossRef
    1. Castro-Rodriguez JA,
    2. Forno E,
    3. Rodriguez-Martinez CE, et al.
    Risk and protective factors for childhood asthma: What is the evidence? J Allergy Clin Immunol Pract 2016; 4: 1111–1122. doi:10.1016/j.jaip.2016.05.003
    OpenUrl
    1. Coultas DB
    . Health effects of passive smoking. 8. Passive smoking and risk of adult asthma and COPD: an update. Thorax 1998; 53: 381–387. doi:10.1136/thx.53.5.381
    OpenUrlFREE Full Text
    1. Uddenfeldt M,
    2. Janson C,
    3. Lampa E, et al.
    High BMI is related to higher incidence of asthma, while a fish and fruit diet is related to a lower – Results from a long-term follow-up study of three age groups in Sweden. Respir Med 2010; 104: 972–980. doi:10.1016/j.rmed.2009.12.013
    OpenUrlCrossRefPubMed
    1. Modig L,
    2. Torén K,
    3. Janson C, et al.
    Vehicle exhaust outside the home and onset of asthma among adults. Eur Respir J 2009; 33: 1261–1267. doi:10.1183/09031936.00101108
    OpenUrlAbstract/FREE Full Text
    1. Caillaud D,
    2. Leynaert B,
    3. Keirsbulck M, et al.
    Indoor mould exposure, asthma and rhinitis: findings from systematic reviews and recent longitudinal studies. Eur Respir Rev 2018; 27: 170137. doi:10.1183/16000617.0137-2017
    OpenUrlAbstract/FREE Full Text
    1. Wang J,
    2. Pindus M,
    3. Janson C, et al.
    Dampness, mould, onset and remission of adult respiratory symptoms, asthma and rhinitis. Eur Respir J 2019; 53: 1801921. doi:10.1183/13993003.01921-2018
    OpenUrlAbstract/FREE Full Text
    1. Quirce S,
    2. Bernstein JA
    . Old and new causes of occupational asthma. Immunol Allergy Clin North Am 2011; 31: 677–698. doi:10.1016/j.iac.2011.07.001
    OpenUrlCrossRefPubMed
    1. Tan J,
    2. Bernstein JA
    . Occupational asthma: an overview. Curr Allergy Asthma Rep 2014; 14: 431. doi:10.1007/s11882-014-0431-y
    OpenUrl
    1. Storaas T,
    2. Zock JP,
    3. Morano AE, et al.
    Incidence of rhinitis and asthma related to welding in Northern Europe. Eur Respir J 2015; 46: 1290–1297. doi:10.1183/13993003.02345-2014
    OpenUrlAbstract/FREE Full Text
    1. Svanes Ø,
    2. Skorge TD,
    3. Johannessen A, et al.
    Respiratory health in cleaners in northern Europe: is susceptibility established in early life? PLoS One 2015; 10: e0131959. doi:10.1371/journal.pone.0131959
    OpenUrl
    1. Garcia-Larsen V,
    2. Del Giacco SR,
    3. Moreira A, et al.
    Asthma and dietary intake: an overview of systematic reviews. Allergy 2016; 71: 433–442. doi:10.1111/all.12800
    OpenUrl
    1. Peters U,
    2. Dixon A,
    3. Forno E
    . Obesity and asthma. J Allergy Clin Immunol 2018; 141: 1169–1179. doi:10.1016/j.jaci.2018.02.004
    OpenUrl
    1. Gunnbjörnsdóttir MI,
    2. Omenaas E,
    3. Gislason T, et al.
    Obesity and nocturnal gastro-oesophageal reflux are related to onset of asthma and respiratory symptoms. Eur Respir J 2004; 24: 116–121. doi:10.1183/09031936.04.00042603
    OpenUrlAbstract/FREE Full Text
    1. Ólafsdottir IS,
    2. Gislason T,
    3. Thjodleifsson B, et al.
    C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study. Thorax 2005; 60: 451–454. doi:10.1136/thx.2004.035774
    OpenUrlAbstract/FREE Full Text
    1. Leinaar E,
    2. Alamian A,
    3. Wang L
    . A systematic review of the relationship between asthma, overweight, and the effects of physical activity in youth. Ann Epidemiol 2016; 26: 504–510. doi:10.1016/j.annepidem.2016.06.002
    OpenUrl
  40. ↵
    1. Cosio BG,
    2. Iglesias A,
    3. Rios A, et al.
    Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of COPD. Thorax 2009; 64: 424–429. doi:10.1136/thx.2008.103432
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Ford PA,
    2. Durham AL,
    3. Russell RE, et al.
    Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010; 137: 1338–1344. doi:10.1378/chest.09-2363
    OpenUrlCrossRefPubMed
  42. ↵
    National Institute for Health and Care Excellence. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. www.nice.org.uk/guidance/ng115/resources/chronic-obstructive-pulmonary-disease-in-over-16s-diagnosis-and-management-pdf-66141600098245 Date last accessed: December 6, 2019; date last updated: August 10, 2020.
  43. ↵
    1. Vogelmeier CF,
    2. Criner GJ,
    3. Martinez FJ, et al.
    Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J 2017; 49: 1700214. doi:10.1183/13993003.00214-2017
    OpenUrlAbstract/FREE Full Text
  44. ↵
    1. Chauhan BF,
    2. Ducharme FM
    . Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children. Cochrane Database Syst Rev 2012; 5: CD002314.
    OpenUrlPubMed
  45. ↵
    1. Dorais M,
    2. Blais L,
    3. Chabot I, et al.
    Treatment persistence with leukotriene receptor antagonists and inhaled corticosteroids. J Asthma 2005; 42: 385–393. doi:10.1081/JAS-200063007
    OpenUrlPubMed
  46. ↵
    Global Initiative for Asthma. Global strategy for asthma management and prevention (updated 2019). https://ginasthma.org/gina-reports/ Date last accessed: March 2, 2020; date last updated: August 10, 2020.
  47. ↵
    Global Initiative for Asthma. Global strategy for asthma management and prevention (updated 2018). https://ginasthma.org/ Date last accessed: December 6, 2019; date last updated: August 10, 2020.
  48. ↵
    1. Anis AH,
    2. Lynd LD,
    3. Wang XH, et al.
    Double trouble: impact of inappropriate use of asthma medication on the use of health care resources. CMAJ 2001; 164: 625–631.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Janson C,
    2. Nwaru B,
    3. Hasvold LP, et al.
    SABA overuse and risk of mortality in a nationwide Swedish asthma cohort (HERA). Eur Respir J 2019; 54: OA2105.
    OpenUrlCrossRef
  50. ↵
    1. Liou JT,
    2. Lin CW,
    3. Tsai CL, et al.
    Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease. Mayo Clin Proc 2018; 93: 1462–1473. doi:10.1016/j.mayocp.2018.05.030
    OpenUrl
  51. ↵
    1. Wise RA,
    2. Chapman KR,
    3. Scirica BM, et al.
    Effect of aclidinium bromide on major cardiovascular events and exacerbations in high-risk patients with chronic obstructive pulmonary disease: The ASCENT-COPD randomized clinical trial. JAMA 2019; 321: 1693–1701. doi:10.1001/jama.2019.4973
    OpenUrl
  52. ↵
    1. Molimard M,
    2. Raherison C,
    3. Lignot S, et al.
    Assessment of handling of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol Med 2003; 16: 249–254. doi:10.1089/089426803769017613
    OpenUrlCrossRefPubMed
  53. ↵
    1. Molimard M,
    2. Raherison C,
    3. Lignot S, et al.
    Chronic obstructive pulmonary disease exacerbation and inhaler device handling: real-life assessment of 2935 patients. Eur Respir J 2017; 49: 1601794. doi:10.1183/13993003.01794-2016
    OpenUrlAbstract/FREE Full Text
  54. ↵
    British Thoracic Society, Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. www.brit-thoracic.org.uk/quality-improvement/guidelines/asthma/ Date last accessed: December 6, 2019.
  55. ↵
    1. Koser A,
    2. Westerman J,
    3. Sharma S, et al.
    Safety and efficacy of fluticasone propionate/salmeterol hydrofluoroalkane 134a metered-dose-inhaler compared with fluticasone propionate/salmeterol diskus in patients with chronic obstructive pulmonary disease. Open Respir Med J 2010; 4: 86–91. doi:10.2174/1874306401004010086
    OpenUrlPubMed
  56. ↵
    1. Brocklebank D,
    2. Ram F,
    3. Wright J, et al.
    Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature. Health Technol Assess 2001; 5: 1–149. doi:10.3310/hta5260
    OpenUrlPubMed
  57. ↵
    1. Chorão P,
    2. Pereira AM,
    3. Fonseca JA
    . Inhaler devices in asthma and COPD - an assessment of inhaler technique and patient preferences. Respir Med 2014; 108: 968–975. doi:10.1016/j.rmed.2014.04.019
    OpenUrlCrossRefPubMed
  58. ↵
    1. Higgins JPT,
    2. Thomas J
    3. Chandler J et al.
    , eds. Cochrane handbook for systematic reviews of interventions version 6.0. Available from: www.training.cochrane.org/handbooks Date last updated: July, 2019; date last accessed: August 10, 2020.
  59. ↵
    1. Wells BJ,
    2. Chagin KM,
    3. Nowacki AS, et al.
    Strategies for handling missing data in electronic health record derived data. EGEMS (Wash DC) 2013; 1: 1035.
    OpenUrl
  60. ↵
    1. Salas M,
    2. Hofman A,
    3. Stricker BH
    . Confounding by indication: an example of variation in the use of epidemiologic terminology. Am J Epidemiol 1999; 149: 981–983. doi:10.1093/oxfordjournals.aje.a009758
    OpenUrlCrossRefPubMed
  61. ↵
    1. Karim ME,
    2. Gustafson P,
    3. Petkau J, et al.
    Comparison of statistical approaches for dealing with immortal time bias in drug effectiveness studies. Am J Epidemiol 2016; 184: 325–335. doi:10.1093/aje/kwv445
    OpenUrlCrossRefPubMed
  62. ↵
    1. Keil AP,
    2. Edwards JK,
    3. Richardson DB, et al.
    The parametric g-formula for time-to-event data: intuition and a worked example. Epidemiology 2014; 25: 889–897. doi:10.1097/EDE.0000000000000160
    OpenUrlCrossRefPubMed
  63. ↵
    1. Garcia-Aymerich J,
    2. Varraso R,
    3. Danaei G, et al.
    Incidence of adult-onset asthma after hypothetical interventions on body mass index and physical activity: an application of the parametric g-formula. Am J Epidemiol 2014; 179: 20–26. doi:10.1093/aje/kwt229
    OpenUrlCrossRefPubMed
  64. ↵
    1. Roche N,
    2. Reddel H,
    3. Martin R, et al.
    Quality standards for real-world research. Focus on observational database studies of comparative effectiveness. Ann Am Thorac Soc 2014; 11: Suppl. 2, S99–104. doi:10.1513/AnnalsATS.201309-300RM
    OpenUrlPubMed
  65. ↵
    1. Jeyaraman MM,
    2. Rabbani R,
    3. Al-Yousif N, et al.
    Inter-rater reliability and concurrent validity of ROBINS-I: protocol for a cross-sectional study. Syst Rev 2020; 9: 12. doi:10.1186/s13643-020-1271-6
    OpenUrl
  66. ↵
    1. Wells GA,
    2. Shea B,
    3. O'Connell D, et al.
    The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. www.ohri.ca/programs/clinical_epidemiology/oxford.asp Date last accessed: August 10, 2020.
  67. ↵
    1. Campbell JD,
    2. Perry R,
    3. Papadopoulos NG, et al.
    The REal Life EVidence AssessmeNt Tool (RELEVANT): development of a novel quality assurance asset to rate observational comparative effectiveness research studies. Clin Transl Allergy 2019; 9: 21. doi:10.1186/s13601-019-0256-9
    OpenUrl
  68. ↵
    1. Bakke PS,
    2. Rönmark E,
    3. Eagan T, et al.
    Recommendations for epidemiological studies on COPD. Eur Respir J 2011; 38: 1261–1277. doi:10.1183/09031936.00193809
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. von Elm E,
    2. Altman DG,
    3. Egger M, et al.
    The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61: 344–349. doi:10.1016/j.jclinepi.2007.11.008
    OpenUrlCrossRefPubMed
  70. ↵
    1. Alexeeff SE,
    2. Litonjua AA,
    3. Sparrow D, et al.
    Statin use reduces decline in lung function: VA Normative Aging Study. Am J Respir Crit Care Med 2007; 176: 742–747. doi:10.1164/rccm.200705-656OC
    OpenUrlCrossRefPubMed
    1. Frost FJ,
    2. Petersen H,
    3. Tollestrup K, et al.
    Influenza and COPD mortality protection as pleiotropic, dose-dependent effects of statins. Chest 2007; 131: 1006–1012. doi:10.1378/chest.06-1997
    OpenUrlCrossRefPubMed
  71. ↵
    1. Mancini GB,
    2. Etminan M,
    3. Zhang B, et al.
    Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006; 47: 2554–2560. doi:10.1016/j.jacc.2006.04.039
    OpenUrlFREE Full Text
  72. ↵
    1. Hothersall E,
    2. McSharry C,
    3. Thomson NC
    . Potential therapeutic role for statins in respiratory disease. Thorax 2006; 61: 729–734. doi:10.1136/thx.2005.057976
    OpenUrlAbstract/FREE Full Text
  73. ↵
    1. Criner GJ,
    2. Connett JE,
    3. Aaron SD, et al.
    Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014; 370: 2201–2210. doi:10.1056/NEJMoa1403086
    OpenUrlCrossRefPubMed
  74. ↵
    1. Ingebrigtsen TS,
    2. Marott JL,
    3. Nordestgaard BG, et al.
    Statin use and exacerbations in individuals with chronic obstructive pulmonary disease. Thorax 2015; 70: 33–40. doi:10.1136/thoraxjnl-2014-205795
    OpenUrlAbstract/FREE Full Text
  75. ↵
    1. Regan EA,
    2. Hokanson JE,
    3. Murphy JR, et al.
    Genetic epidemiology of COPD (COPDGene) study design. COPD 2010; 7: 32–43. doi:10.3109/15412550903499522
    OpenUrlCrossRefPubMed
  76. ↵
    1. Couper D,
    2. LaVange LM,
    3. Han M, et al.
    Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax 2014; 69: 491–494. doi:10.1136/thoraxjnl-2013-203897
    OpenUrlFREE Full Text
  77. ↵
    1. Shaw DE,
    2. Sousa AR,
    3. Fowler SJ, et al.
    Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 2015; 46: 1308–1321. doi:10.1183/13993003.00779-2015
    OpenUrlAbstract/FREE Full Text
  78. ↵
    1. Rennard SI
    . The promise of observational studies (ECLIPSE, SPIROMICS, and COPDGene) in achieving the goal of personalized treatment of chronic obstructive pulmonary disease. Semin Respir Crit Care Med 2015; 36: 478–490. doi:10.1055/s-0035-1555609
    OpenUrl
  79. ↵
    1. Agustí A,
    2. Bel E,
    3. Thomas M, et al.
    Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016; 47: 410–419. doi:10.1183/13993003.01359-2015
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Reddel HK,
    2. Gerhardsson de Verdier M,
    3. Agustí A, et al.
    Prospective observational study in patients with obstructive lung disease: NOVELTY design. ERJ Open Res 2019; 5: 00036-02018. doi:10.1183/23120541.00036-2018
    OpenUrl
PreviousNext
Back to top
Vol 6 Issue 4 Table of Contents
ERJ Open Research: 6 (4)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Observational studies assessing the pharmacological treatment of obstructive lung disease: strengths, challenges and considerations for study design
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Observational studies assessing the pharmacological treatment of obstructive lung disease: strengths, challenges and considerations for study design
Jørgen Vestbo, Christer Janson, Javier Nuevo, David Price
ERJ Open Research Oct 2020, 6 (4) 00044-2020; DOI: 10.1183/23120541.00044-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Observational studies assessing the pharmacological treatment of obstructive lung disease: strengths, challenges and considerations for study design
Jørgen Vestbo, Christer Janson, Javier Nuevo, David Price
ERJ Open Research Oct 2020, 6 (4) 00044-2020; DOI: 10.1183/23120541.00044-2020
Reddit logo Technorati logo Twitter logo Connotea logo Facebook logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Abstract
    • Introduction
    • Comparing guidelines, RCTs and observational study outcomes in obstructive lung disease
    • Future prospects in real-world evidence in asthma/COPD
    • Conclusions
    • Acknowledgements
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • COPD and smoking
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

  • Role of digital health in pulmonary rehabilitation
  • Healthcare experiences of adults with COPD in community care
  • Multimorbidity in bronchiectasis
Show more Reviews

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About ERJ Open Research

  • Editorial board
  • Journal information
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Online ISSN: 2312-0541

Copyright © 2023 by the European Respiratory Society