Temporal Risk of Nonfatal Cardiovascular Events After Chronic Obstructive Pulmonary Disease Exacerbation: A Population-based Study.

Rationale: Cardiovascular events after chronic obstructive pulmonary disease (COPD) exacerbations are recognized. Studies to date have been post hoc analyses of trials, did not differentiate exacerbation severity, included death in the cardiovascular outcome, or had insufficient power to explore individual outcomes temporally.Objectives: We explore temporal relationships between moderate and severe exacerbations and incident, nonfatal hospitalized cardiovascular events in a primary care-derived COPD cohort.Methods: We included people with COPD in England from 2014 to 2020, from the Clinical Practice Research Datalink Aurum primary care database. The index date was the date of first COPD exacerbation or, for those without exacerbations, date upon eligibility. We determined composite and individual cardiovascular events (acute coronary syndrome, arrhythmia, heart failure, ischemic stroke, and pulmonary hypertension) from linked hospital data. Adjusted Cox regression models were used to estimate average and time-stratified adjusted hazard ratios (aHRs).Measurements and Main Results: Among 213,466 patients, 146,448 (68.6%) had any exacerbation; 119,124 (55.8%) had moderate exacerbations, and 27,324 (12.8%) had severe exacerbations. A total of 40,773 cardiovascular events were recorded. There was an immediate period of cardiovascular relative rate after any exacerbation (1-14 d; aHR, 3.19 [95% confidence interval (CI), 2.71-3.76]), followed by progressively declining yet maintained effects, elevated after one year (aHR, 1.84 [95% CI, 1.78-1.91]). Hazard ratios were highest 1-14 days after severe exacerbations (aHR, 14.5 [95% CI, 12.2-17.3]) but highest 14-30 days after moderate exacerbations (aHR, 1.94 [95% CI, 1.63-2.31]). Cardiovascular outcomes with the greatest two-week effects after a severe exacerbation were arrhythmia (aHR, 12.7 [95% CI, 10.3-15.7]) and heart failure (aHR, 8.31 [95% CI, 6.79-10.2]).Conclusions: Cardiovascular events after moderate COPD exacerbations occur slightly later than after severe exacerbations; heightened relative rates remain beyond one year irrespective of severity. The period immediately after an exacerbation presents a critical opportunity for clinical intervention and treatment optimization to prevent future cardiovascular events.

Cause-specific mortality in COPD subpopulations: a cohort study of 339 647 people in England.

BACKGROUND: Identifying correlates of cause-specific mortality in patients with chronic obstructive pulmonary disease (COPD) may aid the targeting of therapies to reduce mortality. We determined factors associated with causes of death in a primary care COPD population. METHODS: Clinical Practice Research Datalink Aurum was linked to Hospital Episode Statistics and death certificate data. People with COPD alive between 1 January 2010 and 1 January 2020 were included. Patient characteristics were defined before the start of follow-up: (a) frequency and severity of exacerbations; (b) emphysema or chronic bronchitis; (c) Global Obstructive Lung Disease (GOLD) groups A-D; and (d) airflow limitation. We used Cox Proportional Hazards regression and competing risks to investigate the association between patient characteristics and risk of all-cause, COPD and cardiovascular (CV) mortality. RESULTS: 339 647 people with COPD were included of which 97 882 died during follow-up (25.7% COPD related and 23.3% CV related). Airflow limitation, GOLD group, exacerbation frequency and severity, and COPD phenotype were associated with all-cause mortality. Exacerbations, both increased frequency and severity, were associated with COPD-related mortality (≥2 exacerbations vs none adjusted HR: 1.64, 1.57-1.71; 1 severe vs none adjusted HR: 2.17, 2.04-2.31, respectively). Patients in GOLD groups B-D had a higher risk of COPD and CV mortality compared with GOLD group A (GOLD group D vs group A, adjusted HR for COPD mortality: 4.57, 4.23-4.93 and adjusted HR for CV mortality: 1.53, 1.41-1.65). Increasing airflow limitation was also associated with both COPD and CV mortality (GOLD 4 vs 1, adjusted HR: 12.63, 11.82-13.51 and adjusted HR: 1.75, 1.60-1.91, respectively). CONCLUSION: Poorer airflow limitation, worse functional status and exacerbations had substantial associations with risk of all-cause mortality. Differing results for CV and COPD-related mortality suggests interventions to prevent mortality may need to target particular characteristics or time points in the disease course.

Eligibility of patients with chronic obstructive pulmonary disease for inclusion in randomised control trials investigating triple therapy: a study using routinely collected data.

BACKGROUND: Randomised control trials (RCTs) with strict eligibility criteria can lead to trial populations not commonly seen in clinical practice. We described the proportion of people with chronic obstructive pulmonary disease (COPD) in England eligible for RCTs investigating treatment with triple therapy. METHODS: MEDLINE and Clinicaltrials.gov were searched for RCTs investigating triple therapy and eligibility criteria for each trial were extracted. Using routinely collected primary care data from Clinical Practice Research Datalink Aurum linked with Hospital Episode Statistics, we defined a population of COPD patients registered at a general practice in England, who were ≥ 40 years old, and had a history of smoking. Inclusion date was January 1, 2020. Patients who died earlier or left the general practice were excluded. Eligibility criteria for each RCT was applied to the population of COPD patients and the proportion of patients meeting each trial eligibility criteria were described. RESULTS: 26 RCTs investigating triple therapy were identified from the literature. The most common eligibility criteria were post-bronchodilator FEV1% predicted 30-80%, ≥ 2 moderate/≥ 1 severe exacerbations 12-months prior, no moderate exacerbations one-month prior and no severe exacerbations three-months prior, and the use of maintenance therapy or ICS use prior to inclusion. After applying each RCT eligibility criteria to our population of 79,810 COPD patients, a median of 11.2% [interquartile range (IQR) 1.8-17.4] of patients met eligibility criteria. The most discriminatory criteria included the presence exacerbations of COPD and previous COPD related medication use with a median of 67.6% (IQR 8.5-73.4) and 63% (IQR 69.3-38.4) of COPD patients not meeting these criteria, respectively. CONCLUSION: Data from these RCTs may not be generalisable to the wider population of people with COPD seen in everyday clinical practice and real-world evidence studies are needed to supplement trials to understand effectiveness in all people with COPD.

Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study.

BACKGROUND: An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation. METHODS: We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization. RESULTS: Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45). Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15). CONCLUSIONS: Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Mortality in non-exacerbating COPD: a longitudinal analysis of UK primary care data.

INTRODUCTION: Non-exacerbating patients with chronic obstructive pulmonary disease (COPD) are a less studied phenotype. We investigated clinical characteristics, mortality rates and causes of death among non-exacerbating compared with exacerbating patients with COPD. METHODS: We used data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics between 1 January 2004 and 31 December 2018. Ever smokers with a COPD diagnosis with minimum 3 years of baseline information were included. We compared overall using Cox regression and cause-specific mortality rates using competing risk analysis, adjusted for age, sex, deprivation, smoking status, body mass index, GOLD stage and comorbidities. Causes of death were identified using International Classification of Diseases-10 codes. RESULTS: Among 67 516 patients, 17.3% did not exacerbate during the 3-year baseline period. Mean follow-up was 4 years. Non-exacerbators were more likely to be male (63.3% vs 52.4%, p<0.001) and less often had a history of asthma (33.9% vs 43.6%, p<0.001) or FEV1<50% predicted (23.7 vs 31.8%) compared with exacerbators. Adjusted HR for overall mortality in non-exacerbators compared with exacerbators was 0.62 (95% CI 0.56 to 0.70) in the first year of follow-up and 0.87 (95% CI 0.83 to 0.91) thereafter. Non-exacerbating patients with COPD died less of respiratory causes than exacerbators (29.2% vs 40.3%) and more of malignancies (29.4% vs 23.4%) and cardiovascular diseases (26.2% vs 22.9%). HRs for malignant and circulatory causes of death were increased after the first year of follow-up. DISCUSSION: In this primary care cohort, non-exacerbators showed distinct clinical characteristics and lower mortality rates. Non-exacerbators were equally likely to die of respiratory, malignant or cardiovascular diseases.

Frequency and severity of respiratory infections prior to COPD diagnosis and risk of subsequent postdiagnosis COPD exacerbations and mortality: EXACOS-UK health care data study.

OBJECTIVE: Little is known about how lower respiratory tract infections (LRTIs) before chronic obstructive pulmonary disease (COPD) are associated with future exacerbations and mortality. We investigated this association in patients with COPD in England. METHODS: Clinical Practice Research Datalink Aurum, Hospital Episode Statistics and Office of National Statistics data were used. Start of follow-up was patient's first ever COPD diagnosis date and a 1-year baseline period prior to start of follow-up was used to find mild LRTIs (general practice (GP) events/no antibiotics), moderate LRTIs (GP events+antibiotics) and severe LRTIs (hospitalised). Patients were categorised as having: none, 1 mild only, 2+ mild only, 1 moderate, 2+ moderate and 1+ severe. Negative binomial regression modelled the association between baseline LRTIs and subsequent COPD exacerbations and Cox proportional hazard regression was used to investigate mortality. RESULTS: In 215 234 patients with COPD, increasing frequency and severity of mild and moderate LRTIs were associated with increased rates of subsequent exacerbations compared with no recorded LRTIs (1 mild adjusted IRR 1.16, 95% CI 1.14 to 1.18, 2+ mild IRR 1.51, 95% CI 1.46 to 1.55, 1 moderate IRR 1.81, 95% CI 1.78 to 1.85, 2+ moderate IRR 2.55, 95% CI 2.48 to 2.63). Patients with 1+ severe LRTI (vs no baseline LRTIs) also showed an increased rate of future exacerbations (adjusted IRR 1.75, 95% CI, 1.70 to 1.80). This pattern of association was similar for risk of all-cause and COPD-related mortality; however, patients with 1+ severe LRTIs had the highest risk of all-cause and COPD mortality. CONCLUSION: Increasing frequency and severity of LRTIs prior to COPD diagnosis were associated with increasing rates of subsequent exacerbations, and increasing risk of all-cause and COPD-related mortality.

Left-sided heart failure burden and mortality in idiopathic pulmonary fibrosis: a population-based study.

BACKGROUND: Cardiovascular disease is prevalent in idiopathic pulmonary fibrosis (IPF), yet the extent of left-sided heart failure (HF) burden, whether this has changed with time and whether HF impacts mortality risk in these patients are unknown. The aims of this study were therefore to determine the temporal trends in incidence and prevalence of left-sided HF in patients with IPF in England and compare these to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as determine the risk of all-cause and cause-specific mortality in patients with comorbid left-sided HF and IPF at population-level using electronic healthcare data. METHODS: Clinical Practice Research Datalink (CPRD) Aurum primary-care data linked to mortality and secondary-care data was used to identify IPF patients in England. Left-sided HF prevalence and incidence rates were calculated for each calendar year between 2010 and 2019, stratified by age and sex. Risk of all-cause, cardiovascular and IPF-specific mortality was calculated using multivariate Cox regression. RESULTS: From 40,577patients with an IPF code in CPRD Aurum, 25, 341 IPF patients met inclusion criteria. Left-sided HF prevalence decreased from 33.4% (95% CI 32.2-34.6) in 2010 to 20.9% (20.0-21.7) in 2019. Left-sided HF incidence rate per 100 person-years (95% CI) remained stable between 2010 and 2017 but decreased from 4.3 (3.9-4.8) in 2017 to 3.4 (3.0-3.9) in 2019. Throughout follow-up, prevalence and incidence were higher in men and with increasing age. Comorbid HF was associated with poorer survival (adjusted HR (95%CI) 1.08 (1.03-1.14) for all-cause mortality; 1.32 (1.09-1.59) for cardiovascular mortality). CONCLUSION: Left-sided HF burden in IPF patients in England remains high, with incidence almost 4 times higher than in COPD, a comparable lung disease with similar cardiovascular risk factors. Comorbid left-sided HF is also a poor prognostic marker. More substantial reduction in left-sided HF prevalence than incidence suggests persistently high IPF mortality. Given rising IPF incidence in the UK, this calls for better management of comorbidities such as left-sided HF to help optimise IPF survival.

Accelerated FEV1 decline and risk of cardiovascular disease and mortality in a primary care population of COPD patients.

Accelerated lung function decline has been associated with increased risk of cardiovascular disease (CVD) in a general population, but little is known about this association in chronic obstructive pulmonary disease (COPD). We investigated the association between accelerated lung function decline and CVD outcomes and mortality in a primary care COPD population.COPD patients without a history of CVD were identified in the Clinical Practice Research Datalink (CPRD)-GOLD primary care dataset (n=36 382). Accelerated decline in forced expiratory volume in 1 s (FEV1) was defined using the fastest quartile of the COPD population's decline. A Cox regression was used to assess the association between baseline accelerated FEV1 decline and a composite CVD outcome over follow-up (myocardial infarction, ischaemic stroke, heart failure, atrial fibrillation, coronary artery disease and CVD mortality). The model was adjusted for age, sex, smoking status, body mass index, history of asthma, hypertension, diabetes, statin use, Modified Medical Research Council (mMRC) dyspnoea score, exacerbation frequency and baseline FEV1 % predicted.6110 COPD patients (16.8%) had a CVD event during follow-up; median length of follow-up was 3.6 years (interquartile range (IQR) 1.7-6.1 years). Median rate of FEV1 decline was -19.4 mL·year-1 (IQR -40.5-1.9); 9095 patients (25%) had accelerated FEV1 decline (> -40.5 mL·year-1), 27 287 (75%) did not (≤ -40.5 mL·year-1). Risk of CVD and mortality was similar between patients with and without accelerated FEV1 decline (HRadj 0.98, 95% CI 0.90-1.06). Corresponding risk estimates were 0.99 (95% CI 0.83-1.20) for heart failure, 0.89 (95% CI 0.70-1.12) for myocardial infarction, 1.01 (95% CI 0.82-1.23) for stroke, 0.97 (95% CI 0.81-1.15) for atrial fibrillation, 1.02 (95% CI 0.87-1.19) for coronary artery disease and 0.94 (95% CI 0.71-1.25) for CVD mortality. Rather, risk of CVD was associated with a mMRC score ≤2 and two or more exacerbations in the year prior.CVD outcomes and mortality were associated with exacerbation frequency and severity and increased mMRC dyspnoea score but not with accelerated FEV1 decline.

Potential impact of diabetes prevention on mortality and future burden of dementia and disability: a modelling study.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of dementia. We estimated the potential impact of trends in diabetes prevalence upon mortality and the future burden of dementia and disability in England and Wales. METHODS: We used a probabilistic multi-state, open cohort Markov model to integrate observed trends in diabetes, cardiovascular disease and dementia to forecast the occurrence of disability and dementia up to the year 2060. Model input data were taken from the English Longitudinal Study of Ageing, Office for National Statistics vital data and published effect estimates for health-state transition probabilities. The baseline scenario corresponded to recent trends in obesity: a 26% increase in the number of people with diabetes by 2060. This scenario was evaluated against three alternative projected trends in diabetes: increases of 49%, 20% and 7%. RESULTS: Our results suggest that changes in the trend in diabetes prevalence will lead to changes in mortality and incidence of dementia and disability, which will become visible after 10-15 years. If the relative prevalence of diabetes increases 49% by 2060, expected additional deaths would be approximately 255,000 (95% uncertainty interval [UI] 236,000-272,200), with 85,900 (71,500-101,600) cumulative additional cases of dementia and 104,900 (85,900-125,400) additional cases of disability. With a smaller relative increase in diabetes prevalence (7% increase by 2060), we estimated 222,200 (205,700-237,300) fewer deaths, and 77,000 (64,300-90,800) and 93,300 (76,700-111,400) fewer additional cases of dementia and disability, respectively, than the baseline case of a 26% increase in diabetes. CONCLUSIONS/INTERPRETATION: Reducing the burden of diabetes could result in substantial reductions in the incidence of dementia and disability over the medium to long term.

Inhaled corticosteroids and FEV1 decline in chronic obstructive pulmonary disease: a systematic review.

Rate of FEV1 decline in COPD is heterogeneous and the extent to which inhaled corticosteroids (ICS) influence the rate of decline is unclear. The majority of previous reviews have investigated specific ICS and non-ICS inhalers and have consisted of randomised control trials (RCTs), which have specific inclusion and exclusion criteria and short follow up times. We aimed to investigate the association between change in FEV1 and ICS-containing medications in COPD patients over longer follow up times.MEDLINE and EMBASE were searched and literature comparing change in FEV1 in COPD patients taking ICS-containing medications with patients taking non-ICS-containing medications were identified. Titles, abstract, and full texts were screened and information extracted using the PICO checklist. Risk of bias was assessed using the Cochrane Risk of Bias tool and a descriptive synthesis of the literature was carried out due to high heterogeneity of included studies.Seventeen studies met our inclusion criteria. We found that the difference in change in FEV1 in people using ICS and non-ICS containing medications depended on the study follow-up time. Shorter follow-up studies (1 year or less) were more likely to report an increase in FEV1 from baseline in both patients on ICS and in patients on non-ICS-containing medications, with the majority of these studies showing a greater increase in FEV1 in patients on ICS-containing medications. Longer follow-up studies (greater than 1 year) were more likely to report a decline in FEV1 from baseline in patients on ICS and in patients on non-ICS containing medications but rates of FEV1 decline were similar.Further studies are needed to better understand changes in FEV1 when ICS-containing medications are prescribed and to determine whether ICS-containing medications influence rate of decline in FEV1 in the long term. Results from inclusive trials and observational patient cohorts may provide information more generalisable to a population of COPD patients.

Using Routinely Collected Electronic Healthcare Record Data to Investigate Fibrotic Multimorbidity in England.

Background: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions). Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death). Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate. Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.

Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.

Risk of cardiovascular events following COVID-19 in people with and without pre-existing chronic respiratory disease.

BACKGROUND: COVID-19 is associated with cardiovascular outcomes in the general population, but it is unknown whether people with chronic respiratory disease (CRD) have a higher risk of cardiovascular events post-COVID-19 compared with the general population and, if so, what respiratory-related factors may modify this risk in these people. METHODS: Primary and secondary care data from the National Health Service England were used to define a population of adults in England with COVID-19 (index date) between 1 January 2020 and 30 November 2021. Adjusted Cox proportional hazard regression was used to quantify the association between CRD, asthma-related factors, chronic obstructive pulmonary disease (COPD)-related factors, and risk of cardiovascular events. Asthma-specific factors included baseline asthma control, exacerbations, and inhaled corticosteroid (ICS) dose. COPD-specific risk factors included baseline ICS and exacerbations. Secondary objectives quantified the impact of COVID-19 hospitalisation and vaccine dose on cardiovascular outcomes. RESULTS: Of 3 670 455 people, those with CRD had a higher risk of cardiovascular events [adjusted hazard ratio (HRadj), 1.08; 95% confidence interval (CI) 1.06-1.11], heart failure (HRadj, 1.17; 95% CI, 1.12-1.22), angina (HRadj, 1.13; 95% CI, 1.06-1.20) and pulmonary emboli (HRadj, 1.24; 95% CI, 1.15-1.33) compared with people without CRD. In people with asthma or COPD, baseline exacerbations were associated with a higher risk of cardiovascular outcomes (HRadj, 1.36; 95% CI, 1.27-1.00 and HRadj, 1.35; 95% CI, 1.24-1.46, respectively). Regardless of CRD, the risk of cardiovascular events was lower with increasing COVID-19 vaccine dose. CONCLUSIONS: Higher risk of cardiovascular events post-COVID-19 might be explained by the underlying severity of the CRD, and COVID-19 vaccines were beneficial to both people with and those without CRD with regards to cardiovascualr events.

Exploring the impact of varying definitions of exacerbations of chronic obstructive pulmonary disease in routinely collected electronic medical records.

BACKGROUND: Validity of exposure and outcome measures in electronic medical records is vital to ensure robust, comparable study findings however, despite validation studies, definitions of variables used often differ. Using exacerbations of chronic obstructive pulmonary disease (COPD) as an example, we investigated the impact of potential misclassification of different definitions commonly used in publications on study findings. METHODS: A retrospective cohort study was performed. English primary care data from the Clinical Practice Research Datalink Aurum database with linked secondary care data were used to define a population of COPD patients ≥40 years old registered at a general practice. Index date was the date eligibility criteria were met and end of follow-up was 30/12/19, death or end of data collection. Exacerbations were defined using 6 algorithms based on definitions commonly used in the literature, including one validated definition. For each algorithm, the proportion of frequent exacerbators (≥2 exacerbations/year) and exacerbation rates were described. Cox proportional hazard regression was used to investigate each algorithm on the association between heart failure and risk of COPD exacerbation. FINDINGS: A total of 315,184 patients were included. Baseline proportion of frequent exacerbators varied from 2.7% to 15.3% depending on the algorithm. Rates of exacerbations over follow-up varied from 19.3 to 66.6 events/100 person-years. The adjusted hazard ratio for the association between heart failure and exacerbation varied from 1.45, 95% confidence intervals 1.42-1.49, to 1.01, 0.98-1.04. INTERPRETATION: The use of high validity definitions and standardisation of definitions in electronic medical records is crucial to generating high quality, robust evidence.

Inhaled Corticosteroids and Risk of Cardiovascular Disease in Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Regression.

Background: Previous studies have reported mixed associations between inhaled corticosteroids (ICSs) and cardiovascular disease (CVD) in people with chronic obstructive pulmonary disease (COPD). Using updated literature, we investigated the association between ICS-containing medications and CVD in COPD patients, stratified by study-related factors. Methods: We searched MEDLINE and EMBASE for studies that reported effect estimates for the association between ICS-containing medications and the risk of CVD in COPD patients. CVD outcomes specifically included heart failure, myocardial infarction, and stroke-related events. We conducted a random-effects meta-analysis and a meta-regression to identify effect-modifying study-related factors. Results: Fifteen studies met inclusion criteria and investigated the association between ICS-containing medications and the risk of CVD. Pooled results from our meta-analysis showed a significant association between ICS-containing medication and reduced risk of CVD (hazard ratio 0.87, 95% confidence intervals 0.78 to 0.97). Study follow-up time, non-ICS comparator, and exclusion of patients with previous CVD modified the association between ICS use and risk of CVD. Conclusions: Overall, we found an association between ICS-containing medications and reduced risk of CVD in COPD patients. Results from the meta-regression suggest that subgroups of COPD patients may benefit from ICS use more than others and further work is needed to determine this.

Inhaled Corticosteroid Withdrawal and Change in Lung Function in Primary Care Patients with Chronic Obstructive Pulmonary Disease in England.

Rationale: In chronic obstructive pulmonary disease (COPD), inhaled corticosteroids (ICS) are associated with pneumonia, highlighting the importance of investigating subgroups of patients who may benefit from prolonged ICS use. Despite this, the WISDOM (Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management) trial found a greater decline in forced expiratory volume in 1 second (FEV1) in patients with COPD who withdrew from ICS compared with patients who remained on triple therapy. Objectives: We investigated the association between ICS withdrawal and the rate of FEV1 decline in patients with COPD using routinely collected electronic healthcare records. Methods: Using CPRD (Clinical Practice Research Datalink) Aurum and Hospital episode statistics, we included patients with COPD who had been on triple therapy for at least 4 months. Patients were categorized into those who withdrew from ICS and those who remained on triple therapy during follow-up. Three cohorts were created: 1) patients meeting the WISDOM trial eligibility criteria; 2) patients with COPD not restricted by the WISDOM trial eligibility criteria; and 3) patients who would have been excluded from the WISDOM trial on the basis of their comorbidities. Mixed linear regression was used to model the association between ICS withdrawal and the rate of FEV1 decline (ml/year) adjusted for baseline characteristics. Results: A total of 6,008 patients with COPD met the WISDOM eligibility criteria, of which 9.0% withdrew from ICS. Mean rates of FEV1 declined -7.8 ml/year (95% confidence interval [CI], -19.7 to 4.1) for withdrawers and -15.2 ml/year (95% CI, -18.7 to -11.8) for those who remained on triple therapy (difference, P = 0.264). A total of 60,645 patients with COPD were not restricted by the WISDOM eligibility criteria. The mean rate of FEV1 decline was -32.6 ml/year (95% CI, -33.6 to -31.5) for withdrawers and -36.4 ml/year (95% CI, -39.4 to -33.4) for those who remained on triple therapy. A total of 32,882 patients with COPD were included in the last population representing those who would have been excluded from the WISDOM trial because of their comorbidities. The mean rate of FEV1 decline was -29.4 ml/year (95% CI, -30 to -28.1) in withdrawers and -31.3 ml/year (95% CI, -35 to -27.5) in those who remained on triple therapy. Conclusions: The rate of FEV1 decline was similar between patients on triple therapy and patients who withdrew from ICS regardless of the specific COPD population studied. In routine clinical practice, few patients with COPD meet WISDOM eligibility criteria, and few patients are withdrawn from ICS.

Frequency and Severity of Exacerbations of COPD Associated with Future Risk of Exacerbations and Mortality: A UK Routine Health Care Data Study.

Background: Studies have shown that chronic obstructive pulmonary disease (COPD) exacerbation events are related to future events; however, previous literature typically reports frequent vs infrequent exacerbations per patient-year and no studies have investigated increasing number of severe exacerbations in relation to COPD outcomes. Objective: To investigate the association between baseline frequency and severity of exacerbations and subsequent mortality and exacerbation risk in a COPD cohort. Methods: Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics data were used to identify patients registered at general practices in the UK, who had a diagnosis of COPD, were over the age of 40 years, were smokers or ex-smokers and had data recorded from 2004 onwards. Frequency and severity of exacerbations in the baseline year were identified as moderate exacerbations (general practice events) and severe exacerbations (hospitalised events). Patients were categorised as having: none, 1 moderate only, 2 moderate only, 3+ moderate only, 1 severe (and any moderate), 2 severe (and any moderate), and 3+ severe (and any moderate exacerbations). Poisson regression was used to investigate the association between baseline exacerbation frequency/severity and exacerbation events and mortality over follow-up. Results: Overall, 340,515 COPD patients were included. Patients had higher rates of future exacerbations with increasing frequency and severity of baseline exacerbations compared to no baseline exacerbations. Adjusted incidence rate ratios (IRR) for patients with 1, 2, and 3+ moderate exacerbations compared to 0 exacerbations were 1.70 (95% CI 1.66-1.74), 2.31 (95% CI 2.24-2.37), and 3.52 (95% CI 3.43-3.62), respectively. Patients with increased frequency of baseline exacerbations were more likely to die from all-cause, COPD-related, and cardiovascular-related mortality in a graduated fashion. Conclusion: Increasing number and severity of exacerbations were associated with increasing risk of subsequent exacerbations, all-cause mortality and COPD-related mortality. Even a single moderate event increases the risk of future events, illustrating that every exacerbation counts.

Deriving a Standardised Recommended Respiratory Disease Codelist Repository for Future Research.

BACKGROUND: Electronic health record (EHR) databases provide rich, longitudinal data on interactions with healthcare providers and can be used to advance research into respiratory conditions. However, since these data are primarily collected to support health care delivery, clinical coding can be inconsistent, resulting in inherent challenges in using these data for research purposes. METHODS: We systematically searched existing international literature and UK code repositories to find respiratory disease codelists for asthma from January 2018, and chronic obstructive pulmonary disease and respiratory tract infections from January 2020, based on prior searches. Medline searches using key terms provided in article lists. Full-text articles, supplementary files, and reference lists were examined for codelists, and codelists repositories were searched. A reproducible methodology for codelists creation was developed with recommended lists for each disease created based on multidisciplinary expert opinion and previously published literature. RESULTS: Medline searches returned 1126 asthma articles, 70 COPD articles, and 90 respiratory infection articles, with 3%, 22% and 5% including codelists, respectively. Repository searching returned 12 asthma, 23 COPD, and 64 respiratory infection codelists. We have systematically compiled respiratory disease codelists and from these derived recommended lists for use by researchers to find the most up-to-date and relevant respiratory disease codelists that can be tailored to individual research questions. CONCLUSION: Few published papers include codelists, and where published diverse codelists were used, even when answering similar research questions. Whilst some advances have been made, greater consistency and transparency across studies using routine data to study respiratory diseases are needed.

Differences in severe exacerbations rates and healthcare utilisation in COPD populations in the UK and France.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality in Europe; however, it is important to understand how clinical practice patterns differ between countries and how this might relate to disease outcomes, to identify ways of improving local disease management. We aimed to describe and compare the management of patients with COPD in the UK and France between 2008 and 2017. METHODS: We used data from the Clinical Practice Research Datalink GOLD and Hospital Episode Statistics in the UK and the Echantillon Généraliste des Bénéficiaire in France to identify patients with COPD each year between 2008 and 2017. We compared patient characteristics, all-cause mortality and COPD exacerbations each year between 2008 and 2017 for patients in the UK and France separately. Health care utilisation and COPD exacerbations in 2017 were compared between France and the UK using t-tests and χ2 tests. RESULTS: Patients with COPD were similar in gender and comorbidities in both countries. Incidence of COPD exacerbations remained stable in the UK and France between 2007 and 2017. In 2017, the proportion of all-cause and COPD-related hospitalisations was greater in the UK than in France (43.9% vs 32.8% and 8.3% vs 4.9%, respectively; p<0.001) as was the proportion of patients visiting accident and emergency (A&E) (39.8% vs 16.2%, respectively; p<0.001). In addition, the mean length of stay in hospital for COPD-related causes was shorter in the UK than in France (6.2 days (SD 8.4) vs 10.5 days (SD 9.1), respectively; p<0.001). DISCUSSION: Overall, UK patients were more likely to go to A&E, be hospitalised for COPD-related causes and stay in hospital for fewer days after being admitted for COPD-related reasons compared with patients in France, illustrating a difference in health-seeking behaviours and access to healthcare.

Challenges and Pitfalls of Using Repeat Spirometry Recordings in Routine Primary Care Data to Measure FEV1 Decline in a COPD Population.

BACKGROUND: Electronic healthcare records (EHR) are increasingly used in epidemiological studies but are often viewed as lacking quality compared to randomised control trials and prospective cohorts. Studies of patients with chronic obstructive pulmonary disease (COPD) often use the rate of forced expiratory volume in 1 second (FEV1) decline as an outcome; however, its definition and robustness in EHR have not been investigated. We aimed to investigate how the rate of FEV1 decline differs by the criteria used in an EHR database. METHODS: Clinical Practice Research Datalink and Hospital Episode Statistics were used. Patient populations were defined using 8 sets of criteria around repeated FEV1 measurements. At a minimum, patients had a diagnosis of COPD, were ≥35 years old, were current or ex-smokers, and had data recorded from 2004. FEV1 measurements recorded during follow-up were identified. Thereafter, eight populations were defined based on criteria around: i) the exclusion of patients or individual measurements with potential measurement error; ii) minimum number of FEV1 measurements; iii) minimum time interval between measurements; iv) specific timing of measurements; v) minimum follow-up time; and vi) the use of linked data. For each population, the rate of FEV1 decline was estimated using mixed linear regression. RESULTS: For 7/8 patient populations, rates of FEV1 decline (age and sex adjusted) were similar and ranged from -18.7mL/year (95% CI -19.2 to -18.2) to -16.5mL/year (95% CI -17.3 to -15.7). Rates of FEV1 decline in populations that excluded patients with potential measurement error ranged from -79.4mL/year (95% CI -80.7 to -78.2) to -46.8mL/year (95% CI -47.6 to -46.0). CONCLUSION: FEV1 decline remained similar in a COPD population regardless of number of FEV1 measurements, time intervals between measurements, follow-up period, exclusion of specific FEV1 measurements, and linkage to HES. However, exclusion of individuals with questionable data led to selection bias and faster rates of decline.