Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks
A recently published retrospective cohort study, supported by REG and Optimum Patient Care (OPC), has found no evidence that initiating either inhaled corticosteroids (ICS) or leukotriene receptor antagonists (LTRA) in preschool children with a history of wheeze or asthma reduces wheezing or asthma attacks.
The study, conducted on behalf of the REG Child Health Working Group, examined UK medical record data of a diverse population of preschool children with at least two previous wheezing episodes. In these children, there were no statistically significant differences in the odds of wheezing/asthma attacks between matched cohorts receiving ICS compared with short-acting β-agonists (SABA) (odds ratio: 1.01 [95% confidence intervals: 0.85-1.19]) or between those receiving LRTA compared with SABA (odds ratio: 1.28 [95% confidence intervals: 0.96-1.72]).
Abstracts from the 2018 Respiratory Effectiveness Group Summit
The Respiratory Effectiveness Group Summit was held in Amsterdam in 2018. The meeting saw international delegates from multiple disciplines come together to discuss respiratory disease and the role of real-world evidence.
The three-day meeting included working group meetings, plenary sessions and debates as well as abstract presentations on recent developments in respiratory research. In December 2018, the abstracts from the summit were published in Respiratory Research. Abstracts included methodological concepts and results for prospective cohorts, retrospective database studies and registries such as the International Severe Asthma Registry (ISAR). Results were also presented from questionnaire-based surveys such as a pharmacy-based patient survey on allergic rhinitis medication; and an international survey of ILD physicians regarding ILD diagnostic practice.
Antibiotic choice and duration associated with repeat prescriptions in infective asthma exacerbations and in lower respiratory tract infections in primary care
Two recent study, for which REG was a collaborator, have shown that the antibiotic choice and prescription duration have an impact on the outcomes of patients, in both lower respiratory tract infections (LRTI) and infective asthma exacerbations.
Both studies used the Optimum Patient Care Research Database (OPCRD) in a cross-sectional design to investigate treatment patterns following the first prescription of an antibiotic. For LRTIs, prescription of antibiotics other than amoxicillin was strongly associated with repeat prescriptions, although the effect size was small (odds ratio 1.15; p<0.001). For infective asthma exacerbations, prescription of a seven day course of amoxicillin was associated with fewer repeat prescriptions.
4 September 2018
Performance of database-derived severe exacerbations and asthma control measures in asthma
In August 2018, a study supported by REG and OPRI to evaluate the clinical utility of database outcomes for asthma was published in Pragmatic and Observational Research. The study found that there was fair agreement between database-recorded and patient-reported asthma exacerbations and that database-derived asthma control and exacerbation outcomes improved following the initiation of inhaled corticosteroids (ICS), while short-acting beta agonist prescriptions did not show this improvement.
While outcome measures in randomised controlled trials are well scrutinised, database-derived outcomes in observational studies have not been critically appraised to the same degree. The evaluation and standardisation of database-derived outcomes allows for more refined studies and more reliable interpretation of results. This study used data from the Optimum Patient Care Research Database (OPCRD) to show that the database-derived outcomes were responsive to ICS treatment, and may therefore be useful in the evaluation of real-life asthma treatment effectiveness and future exacerbation risk.
27 August 2018
Applying UK real-world primary care data to predict asthma attacks in 3776 well-characterised children: A retrospective cohort study
In July 2018, a study published in Primary Care Respiratory Medicine reported that the strongest predictor of future asthma in a cohort of well-characterised children was past asthma attacks. The analysis, funded by REG, also found that higher treatment step, younger age, presence of lower respiratory tract infections, reduced peak flow and an eosinophil count less than 400/µl were associated with a small increase in risk of asthma attack, but did not substantially improve the ability to predicting attacks.
Asthma attacks in children are very common, affecting approximately half of children with asthma each year. However, the predictors of these attacks are not well understood. While poor control may be a predictor of future asthma attacks, the relationship is weak. Furthermore, studies investigating asthma attack predictors often either have small patient numbers or a poorly characterised population.
This recent study used a well-characterised cohort of 3776 children obtained from the Clinical Practice Research Datalink (CPRD) and Optimum Patient Care Research Database (OPCRD), and provides good evidence that the strongest predictor of asthma attacks is previous asthma attacks. Further research is now required to determine if early review and intervention following an asthma attack could reduce the risk of future asthma attacks.
Extrafine Versus Fine Inhaled Corticosteroids in Relation to Asthma Control: A Systematic Review and Meta-Analysis of Observational Real-Life Studies
In June 2018, a study jointly supported by the Respiratory Effectiveness Group (REG) and the Observational and Pragmatic Research Institute (OPRI) was published on behalf of the REG Small Airways Working Group. This systematic review and meta-analysis found that asthma patients treated with extra-fine particle inhaled corticosteroids (ICS) have significantly higher odds of achieving asthma control with lower exacerbation rates at lower ICS doses than those treated with fine-particle ICS.
The study searched the published literature for observational real-life studies investigating asthma and ICS between January 2004 and June 2016. In total, 4248 studies were identified, of which seven met the eligibility criteria for inclusion. Six of the studies were database studies, while one was a prospective cohort study. Pooled analysis of the 33,453 subjects revealed that the odds of asthma control were 1.34 (95% CI, 1.22-1.46) times higher, though there was a high degree of heterogeneity between studies. The analysis also found that the exacerbation rate and ICS dose were significantly lower in those receiving extra-fine ICS compared to those receiving fine ICS (rate ratio 0.84, 95% CI, 0.73-0.97; and weighted mean difference −170 μg, 95% CI, −222 to −118 μg, respectively).
6 June 2018
More testing for alpha-1 antitrypsin deficiency is needed in the UK
Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and the third leading cause of death worldwide. Alpha-1-antitrypsin (AAT) deficiency significantly increases the risk of developing COPD. AAT deficiency (AATD) is a genetic disorder characterized by low serum levels of AAT, which at normal levels protects the lung alveoli from damage. Severe AATD can lead to pulmonary emphysema. Global guidance from the World Health Organization, European Respiratory Society and the Global Initiative for Chronic Obstructive Lung Disease recommends testing AAT levels in blood serum of all COPD patients.
In the UK, previous estimates of the prevalence of AATD are outdated and suggest that it is underdiagnosed. In May 2018, a REG study was published in the European Respiratory Journal that determined recent trends in testing and diagnosing AATD among COPD patients in the UK from 1990 to 2014. The Optimum Patient Care Research Database was used to identify patients with a diagnostic code for COPD from about 550 UK general practices. Analysis focused on those diagnosed with COPD before the age of 60 years.
The study identified over 100,000 patients with COPD, of whom over a quarter were diagnosed before 60 years of age. Between 1994 and 2013 the incidence of AATD diagnosis increased among all age groups and both genders, mostly due to an increase in new testing for AATD from around 0% in 1994 to around 1.3% in 2013. However, despite the increase in testing, still only 2.2% of COPD diagnosed before the age of 60 were ever tested for AATD in the period 1990-2014. Of those tested, 24% were diagnosed with AATD. These findings indicate that AATD remains markedly underdiagnosed in COPD patients in the UK and that more testing is needed.
- Soriano JB, Lucas SJ, Jones R, Miravitlles M, Carter V, Small I, Price D, Mahadeva R. Trends of testing for and diagnosis of alpha-1 antitrypsin deficiency in the UK: more testing is needed. Eur Respir J. 2018 May 31. pii: 1800360.
Harmonizing the nomenclature for therapeutic aerosol particle size: A proposal
In April 2018, Letter to the editor was published in the Journal of Aerosol Medicine and Pulmonary Drug Delivery from the REG Small Airways Working Group. The letter called for the harmonization of the particle size nomenclature used to describe inhaled medications for asthma and COPD. While there are many factors influencing the deposition of these inhaled drugs in the lung, particle size is an important determinant. Given the influence that particle size has on the effectiveness of inhaled treatments, the REG Small Airways Working Group believes a common language is warrented. They have suggested the terms “extrafine”, “fine” and “coarse” be used to describe particle with a mass median aerodynamic diameter of <2.1µm, 2.1-5µm and >5µm respectively, both in product descriptions and in the design and reporting of research in this area.
COPD Baseline Control
In Chronic Obstructive Pulmonary Disease (COPD) the aim of treatment is to reduce symptoms and the occurrence of acute exacerbations. The concept of control in COPD has been developed to guide treatment decisions and indicate prognosis. COPD can be considered controlled if the disease is demonstrated to have both a low impact (i.e. a low level of symptoms) and clinical stability (i.e. no exacerbations or deterioration in COPD Assessment Test (CAT)/ Clinical COPD Questionnaire (CCQ) scores)1.
This concept of control requires validation; hence the REG COPD Working Group have begun an international, multicentre, prospective study, following COPD patients over a 21-month period. An analysis of the data collected from 314 patients during the screening and baseline visits has recently published in Respiratory Medicine.
Most patients in the study are being managed in specialised centres (85%), while the remainder are managed in primary care. The mean age of the patients was 68.5 years, 73% were male, mean FEV1 was 53% of predicted, and based on the BODEx index (Body mass index, Obstruction, Dyspnea and Exacerbations) 88% were classified as having mild-moderate COPD and 12% as severe COPD. According to the prespecified criteria 21% of patients were classified as controlled, all of them with mild-moderate COPD. The main reasons for patients not being classified as controlled were having a high level of dyspnea, a high CAT score or an exacerbation in the previous 3 months. Being female, having chronic bronchitis and having exacerbations in the previous year were associated with having uncontrolled COPD.
These initial study findings suggest the currently proposed criteria for clinical control in COPD are too restrictive. It is hoped the follow-up phase of this prospective study will allow the criteria for control to be refined to improve their ability to predict poor outcomes.
- Soler-Cataluña JJ, Alcazar-Navarrete B, Miravitlles M. The concept of control in COPD: a new proposal for optimising therapy. Eur Respir J. 2014; 44: 1072-1075.
Risk of pneumonia in obstructive lung disease: A real-life study comparing extra-fine and fine-particle inhaled corticosteroids
An REG study published in June 2017 in PLOS one found has found that patients with obstructive lung disease stepping-up their ICS therapy to extra-fine particle ICS are less likely to have pneumonia than those stepping up to fine ICS.
Inhaled corticosteroids (ICS) are widely used in high doses to treat obstructive lung disease such as asthma and chronic obstructive pulmonary disease. Despite their frequent use, there is concern regarding inappropriate prescribing of high-dose ICS and the potential consequences of regular use, including an increased risk of pneumonia. While it is known that regular ICS use in those with obstructive lung disease is linked with an increased risk of pneumonia, the effect of ICS-particle size on this risk was not known.
This REG study aimed to clarify the risks by performing a retrospective cohort analysis of the UK Optimum Patient Care Research Database (OPCRD; www.optimumpatientcare.org). The study analysed a cohort of patients with obstructive lung disease who were prescribed ICS and had their ICS therapy stepped up (≥50% dose increase). The risk of pneumonia was compared in those stepping up as extra-fine particle ICS with those stepping up as fine particle ICS, controlling for prescribed dose. It also examined the effect of stepping up as fine versus extra-fine particle ICS on acute exacerbations and respiratory events.
The study concluded that patients with obstructive lung disease stepping-up their ICS therapy to extra-fine particle ICS are less likely to have pneumonia or adverse respiratory outcomes than those stepping up to fine ICS. While the effects of extra-fine versus fine particle size on risk of pneumonia were statistically significant in unmatched analysis (odds ratio=0.6, p<0.011), in matched analysis controlling for COPD diagnosis, the effects were less pronounced (odds ratio=0.5, p=0.054). Patients on daily ICS doses in excess of 700 mcg (fluticasone propionate equivalent) were also found to have a significantly increased risk of pneumonia compared with patients on lower doses, irrespective of particle size.
Blood eosinophil count and exacerbation risk in patients with COPD
Chronic obstructive pulmonary disease (COPD) is an important public health challenge as it is a major cause of chronic morbidity and the 4th leading cause of death worldwide1. In patients with COPD, exacerbations are a major contributor to worsening lung function, impaired quality of life, emergency healthcare use and COPD-related mortality. A large observational study, led by Prof. David Price of the Observational and Pragmatic Research Institute and supported by the Respiratory Effectiveness Group (REG), helps to identify those at increased risk of COPD exacerbations.
This research uses the Optimum Patient Care Research Database (OPCRD; www.optimumpatientcare.org), which comprises a large patient population drawn from geographically and socioeconomically diverse practices throughout the UK. The benefit of this approach is the inclusion of a diverse spectrum of COPD patients, many of whom would not meet the eligibility criteria for randomised controlled trials despite being representative of those regularly seen by clinicians.
In ex-smokers with stable COPD an elevated blood eosinophil count was associated with higher rate of exacerbations in the following year. No increase in exacerbation rate was seen with elevated eosinophil levels in current smokers. The increased exacerbation rate with elevated blood eosinophil levels was found in patients treated with ICS, which is consistent with previous research where ICS treatment failed to lower the blood eosinophil count2.
These findings, published in the European Respiratory Journal, identify a population, ex-smokers with stable COPD but elevated eosinophil levels, where a specific treatment of eosinophilic inflammation may be beneficial in minimising the risk for individual patients.
- Lozano R, Naghavi M, Foreman, K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012; 380 (9859):2095-128
- Barnes NC, Sharma R, Lettis S, et al. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J. 2016; 47: 1374–1382.
Validating the Concept of COPD Control
Chronic Obstructive Pulmonary Disease (COPD) is a major cause of chronic morbidity and mortality worldwide. COPD is considered to be controlled if treatment is minimising symptoms and reducing the risk of acute exacerbations. The concept of control in COPD has been developed as a tool to aid physicians in modifying individual patient’s treatment in order to optimise the patient’s outcomes.
This REG study, published in COPD: Journal of Chronic Obstructive Pulmonary Disease, has investigated the association between COPD control status and clinical outcomes. A retrospective, observational cohort study was conducted using electronic medical records and linked patient questionnaire data from the UK Optimum Patient Care Research Database (OPCRD).
When using the definition of COPD control proposed by Soler-Cataluña et al (2014)1, it was found that only a small proportion of patients in this UK study could be classed as having controlled COPD. Despite this the UK patient population did not have an increased risk of exacerbations, indicating that the proposed definition of control may be too strict.
Patients with mild to moderate COPD that were categorised as having uncontrolled disease experienced exacerbations sooner than patients with controlled disease.
This finding highlights the importance of having a measure of control in COPD; identifying those patients with uncontrolled disease allows treatment to be stepped up so that future exacerbations are reduced. However, the results of this study suggest that further work is still required to optimise the sensitivity and specificity of the proposed COPD control definition.
- Soler-Cataluña JJ, Alcazar-Navarrete B, Miravitlles M. The concept of control in COPD: a new proposal for optimising therapy. Eur Respir J. 2014; 44:1072–1075.
Evidence for Health Decision Making – Beyond Randomised Controlled Trials
In August 2017, the New England Journal of Medicine published a review of the use of randomised controlled trials (RCTs) and observational studies by Thomas R Frieden, former Director of the US Centres for Disease Control and Prevention. The author highlights some of the known issues with RCTs and calls for the improved use of multiple data sources in decision making. Using examples ranging from influenza vaccines to type 2 diabetes treatments, the author sets out a compelling argument for the use of observational studies and real world evidence to supplement, support and strengthen evidence garnered from RCTs. The review also highlights specific scenarios where conducting an observational study may be more appropriate than conducting an RCT.
The Respiratory Effectiveness Group welcomes this article, and its recognition of the role of real life data can play in improving the evidence base for clinical practice.
“Elevating RCTs at the expense of other potentially highly valuable sources of data is counterproductive. A better approach is to clarify the health outcome being sought and determine whether existing data are available that can be rigorously and objectively evaluated, independently of or in comparison with data from RCTs, or whether new studies (RCT or otherwise) are needed”.