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Axson et al. Heart failure in the COPD population

Temporal trends in the incidence of heart failure among patients

with COPD and its impact on mortality

Authors

Eleanor L Axson MPH1*, Varun Sundaram MD1, 2, Chloe I Bloom PhD1, Alex Bottle PhD3, Martin R Cowie

MD1, Jennifer K Quint PhD1

Affiliations1 National Heart and Lung Institute, Imperial College London, London, UK

2 Harrington Heart and Vascular Institute, University Hospitals Cleveland Medical Centre, Case Western

Reserve University, Cleveland, USA

3 Dr Foster Unit, Department of Primary Care and Public Health, Imperial College London, London, UK

*Corresponding Author

Eleanor L Axson MPH AFHEA

G05 Emmanuel Kaye Building

National Heart and Lung Institute

Imperial College London

Manresa Road

London, SW3 6LR

United Kingdom

E-mail: [email protected]

Telephone: +44 (0) 207 594 7987

Author Contribution

ELA conducted the analyses and drafted the manuscript. VS aided in the drafting of the manuscript. CIB, AB,

MRC, and JKQ contributed to the design of the study and revision of the manuscript. ELA is the guarantor.

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Funding

This work was not funded by any particular entity.

Conflicts of Interest

Miss Axson and Dr Sundaram have nothing to disclose. Dr Bloom reports grants from AstraZeneca, grants from

Chiesi, grants from Asthma UK, outside the submitted work. Dr Bottle reports grants from Dr Foster, during the

conduct of the study; grants from Medtronic, outside the submitted work. Prof Cowie reports receiving research

funding and speaker fees from ResMed, Boston Scientific, Medtronic, and Abbott and consultancy and speaker

fees from Servier, Novartis, Vifor, LivaNova, Pfizer, Roche Diagnostics, and Amgen, outside the submitted

work. Dr Quint reports grants from MRC, grants from BLF, grants from The Health Foundation, grants and

personal fees from AZ, grants and personal fees from BI, grants from Chiesi, grants and personal fees from

Bayer, grants and personal fees from GSK, outside the submitted work.

Disclaimer

This research was supported by the National Institute for Health Research (NIHR) Imperial Biomedical

Research Centre (BRC). The views expressed are those of the authors and not necessarily those of the NIHR or

the Department of Health and Social Care. This study is based in part on data from the Clinical Practice

Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare products Regulatory

Agency. The data is provided by patients and collected by the National Health Service (NHS) as part of their

care and support. The Office for National Statistics (ONS) was the provider of the ONS Data contained within

the CPRD Data and maintains a Copyright © 2019, re-used with the permission of The Health & Social Care

Information Centre, all rights reserved. The interpretation and conclusions contained in this study are those of

the authors alone.

Data sharing

Data are available on request from the Clinical Practice Research Datalink (CPRD). Their provision requires the

purchase of a license and our license does not permit us to make them publicly available to all. We used data

from the version collected in January 2018 and have clearly specified the data selected in our Methods section.

To allow identical data to be obtained by others, via the purchase of a license, we will provide the code lists on

request. Licences are available from the CPRD (http://www.cprd.com): The Clinical Practice Research Datalink

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Group, The Medicines and Healthcare products Regulatory Agency, 10 South Colonnade, Canary Wharf,

London E14 4PU.

Subject Category

9.4 COPD: Comorbidities

MeSH

Comorbidity, Epidemiology, Cause of Death

Word Count

3,732 words

This article has an online supplement, which is accessible from this issue's table of contents online at

www.atsjournals.org.

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Abstract

Rationale

Heart failure (HF) is a common comorbidity in the chronic obstructive pulmonary disease (COPD) population,

but previous research has shown under recognition.

ObjectivesTo determine the incidence of HF in a prevalent COPD cohort. To determine the impact of incident HF on

short- and long-term mortality of patients with COPD.

Methods

Crude incidence of HF in the HF-naïve primary care COPD population was calculated for each year from 2006-

2016 using UK data from the Clinical Practice Research Datalink (CPRD). Patients with COPD were identified

using a validated code list and were required to be over 35 years old at COPD diagnosis, have a history of

smoking, and have documented airflow obstruction. Office of National Statistics provided mortality data for

England. Adjusted mortality rate ratios (aMRR) from Poisson regression were calculated for patients with

COPD and incident HF (COPD-iHF) in 2006, 2011, and 2015 compared temporally and with patients with

COPD and without incident HF (COPD-no HF) in those years. Regression was adjusted for age, sex, BMI,

severity of airflow limitation, smoking status, history of cardiovascular disease, and diabetes.

ResultsWe identified 95,987 HF-naïve patients with COPD. Crude incidence of HF was steady from 2006-2016 (1.18

per 100 person-years (95%CI: 1.09, 1.27)). Patients with COPD-iHF experienced greater than threefold increase

in one-year mortality and twofold increase in five-year and 10-year mortality compared with patients with

COPD-no HF, with no change based on year of HF diagnosis. Mortality of patients with COPD-iHF did not

improve over time, comparing incident HF in 2011 (1-year aMRR 1.26, 95%CI: 0.83, 1.90; 5-year aMRR 1.26,

95%CI: 0.98, 1.61) and 2015 (1-year aMRR 1.63, 95%CI: 0.98, 2.70) with incident HF in 2006.

Conclusions

The incidence of HF in the UK COPD population was stable in the last decade. Survival of patients with COPD

and incident HF has not improved over time in England. Bespoke guidelines for the diagnosis and management

of HF in the COPD population are needed to improve identification and survival of patients.

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Introduction

Chronic obstructive pulmonary disease (COPD) and heart failure (HF) are both systemic disorders that share

risk factors and pathophysiological pathways, with the ability of either condition to exacerbate the other leading

to increased healthcare costs (1-3). Patients with COPD have an increased risk of developing HF, particularly

HF with preserved ejection fraction (4, 5), and this could be attributed to common risk factors (e.g. smoking),

COPD-driven systemic inflammation, and the high prevalence of HF precursors (e.g. diabetes, hypertension,

atrial fibrillation, and ischaemic heart disease) in patients with COPD (6-9).

The crude incidence of HF, inclusive of all types, has increased in the general UK population (10), whereas the

crude incidence of COPD has remained steady in the UK since 2008 (11). There is a large body of literature to

suggest that the presence of COPD may hinder subsequent diagnosis of HF, as symptoms commonly associated

with HF overlap with those of COPD (e.g., breathlessness, nocturnal cough and paroxysmal nocturnal

dyspnoea) (12, 13). Studies have found anywhere from 10-46% previously unrecognised left HF with left

ventricular dysfunction in COPD populations (14). Additionally, research is divided as to how incident HF

impacts mortality in COPD patients. Newly diagnosed HF was found to significantly increase all-cause

mortality in patients with COPD in one study (15); contrastingly, another study found no significant impact of

incident HF on all-cause mortality among patients with COPD (16).

In order to assess whether the proportion of patients with COPD with diagnosed HF has changed over time, and

therefore whether HF detection within the COPD population has improved, we determined the annual incidence

of HF in the primary care COPD population in the UK from 2006 to 2016. Additionally, we investigated the

impact of incident HF on short- and long-term mortality and on the underlying cause of death among patients

with COPD in England.

Methods

Data source

Data were obtained from the Clinical Practice Research Datalink (CPRD), a primary care database of

anonymised electronic health records from general practitioners representing 6.9% of the UK population and

representative in terms of sex, age, body mass index (BMI), and ethnicity (17). Linked pseudonymised mortality

data from the Office for National Statistics (ONS), socioeconomic data from the Index of Multiple Deprivation

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(IMD), and secondary care data from Hospital Episode Statistics (HES) were provided for this study by CPRD

for patients in England. Data is linked by NHS Digital, the statutory trusted third party for linking data, using

identifiable data held only by NHS Digital. Select general practices consent to this process at a practice level,

with individual patients having the right to opt-out. Use of HES and ONS data is Copyright © (2018), re-used

with the permission of The Health & Social Care Information Centre, all rights reserved.

Case ascertainment and exposure

We used a validated code list to identify patients with COPD within CPRD from 2006 to 2016 (18). Patients

were required to have acceptable data for research as determined by CPRD. Patients must have had a COPD

diagnosis over the age of 35 years, a history of smoking, and documented airflow obstruction (forced expiratory

volume in 1 second/forced vital capacity ratio (FEV1/FVC) < 0.70) per UK guidelines (19). HF was identified

using a code list created by clinicians (Table E1). All patients with a diagnosis of HF (prevalent HF) prior to the

start of follow up were excluded. Patients with incident HF were defined as those for whom the first occurrence

of a HF diagnostic code in primary care occurred during the study period, 2006-2016. The start of follow-up

was defined as the latest date of the following: 1) the date from which practice data was deemed eligible for

research per CPRD, 2) the date from which the patient has continuous data, 3) the patient’s 35 th birthdate, 4) the

start of the study on 01 January 2006, or 5) the date of COPD diagnosis.

Covariates

The most recent measures for baseline characteristics were obtained at start of follow-up on 01 January 2006.

BMI, in kg/m2, was measured continuously. Smoking was categorised as ‘current smoker’ and ‘former smoker’.

Severity of airways limitation, within +/- 2 years of start of follow-up, was graded based on the Global Initiative

for Chronic Obstructive Lung Disease (GOLD) guidelines and grouped as GOLD1 (mild), GOLD2 (moderate),

GOLD3 (severe), and GOLD4 (severe-very severe) (20), validity of spirometry values has been previously

assessed as high quality in CPRD (21). History of cardiovascular disease included prior diagnosis of ischaemic

heart disease, peripheral artery disease, atrial fibrillation, hypertension, and/or stroke.

Statistical analyses

Baseline characteristics were expressed using mean ± standard deviation for continuous variables and

percentages for categorical variables. We calculated sex, age group (35-64, 65-74, 75-84, and 85+ years),

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smoking status, and GOLD- specific, HF incidence rates per 100 person years at risk for each year (2006-2016)

in patients with COPD.

To isolate the effect of incident HF on mortality, we calculated crude mortality rate ratios (MRR) by comparing

mortality rates at 1, 5 and 10 years of follow-up of patients with COPD with incident HF (COPD-iHF) versus

patients with COPD without incident HF (COPD-no HF) for the same time period. For example, patients with

COPD with HF diagnosed in 2006 were followed for 1-year, 5-year, and 10-year mortality and compared to

patients with COPD without HF diagnosed in 2006. A Kaplan-Meier survivor curve was produced comparing

patients with COPD with and without incident HF diagnosis in 2006 over 10 years of follow-up. Furthermore,

adjusted mortality rate ratios (1-, 5- and 10-year rates) of patients with COPD with and without incident HF

were calculated stratified by GOLD. Censoring was defined as death, transfer from practice, last date for which

practice data was available, last date for which linked ONS data was available, or the end of the study (Figure

E1).

For the analysis of temporal trends in the short term mortality rates of patients with COPD-iHF, crude MRR

were calculated comparing 1-year mortality rates of patients with COPD-iHF in 2011 and 2015, with patients

with COPD-iHF in 2006 as the reference. Additionally, trends in long-term mortality rates (i.e., 5-year mortality

rates) were evaluated by comparing 5-year mortality rates of patients with COPD-iHF in 2011 with the 5-year

mortality rate of patients with COPD-iHF in 2006. This analysis was performed to evaluate the changes in the

management of incident HF over a decade among patients with COPD. Mortality rate ratios adjusted for age,

sex, BMI, GOLD, smoking status, history of cardiovascular disease, and diabetes (aMRR) were estimated using

Poisson regression. Robust variance estimates were used in the Poisson regression to account for clustering on

general practice (GP).

Cause of death

ONS mortality data was analysed to assess the trends in the cause of death for COPD-iHF and COPD-no HF

over a decade (2006-2010 and 2011-2016). Cause of death by severity of airflow limitation (GOLD1-2 vs

GOLD3-4) was also assessed from 2006-2016 for COPD-iHF in 2006. ONS derives the underlying cause of

death from death certificates using standardised guidelines and coded using the International Statistical

Classification of Diseases and Related Health Problems 10th Revision (ICD-10) (22).

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Ethics approval

Protocols for this research were approved by the Independent Scientific Advisory Committee (ISAC) for

MHRA Database Research (protocol numbers: 18_006R2 and 18_074RARA2) and the approved protocols were

made available to the journal and reviewers during peer review. Generic ethical approval for observational

research using the CPRD with approval from ISAC has been granted by a Health Research Authority (HRA)

Research Ethics Committee (East Midlands – Derby, REC reference number 05/MRE04/87).

Results

Baseline Characteristics

We identified 95,987 patients with COPD without a HF diagnosis at the start of follow-up (Figure 1). Patients

with COPD-iHF were more likely to be older, male, obese, former smokers and have moderate to severe airflow

limitation (Table 1) compared to patients with COPD-no HF. Patients with COPD-iHF were more likely to have

traditional risk factors for HF including atrial fibrillation, diabetes, hypertension, and vascular disease

(ischaemic heart disease and/or peripheral artery disease) at the start of follow-up. Average length of follow up

and the descriptive information regarding the 2006, 2011, and 2015 COPD-iHF cohorts and their comparator

COPD-no HF cohorts are outlined in Tables E2-E5.

Incidence of HF among patients with COPD

The crude incidence of HF in the COPD population was steady from 2006 to 2016 (Figure 2; Supplementary

Table 6), averaging 1.18 per 100 person-years (95%CI: 1.09, 1.27). The incidence of HF was higher for males

compared with females, at older ages, for former smokers compared with current smokers, and for patients with

higher airflow limitation (GOLD3-4 vs GOLD1-2) (Tables E7-E10).

Mortality

Comparison of mortality rates; COPD-iHF vs COPD-no HF

The crude 1-year, 5-year, and 10-year mortality rates for patients with COPD-iHF and COPD-no HF in 2006,

2011, and 2015, as appropriate, can be found in Supplementary Tables 11-13. In 2006, patients with COPD-iHF

experienced over three times greater 1-year mortality than patients with COPD-no HF (Figure 3a; Table E14).

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The trends where similar in 2011 and 2015 (Figure 3a; Table E14). Patients with COPD-iHF in 2006

experienced a greater than two-fold increase in 5-year mortality compared with COPD-no HF in 2006, with

similar trends observed in 2011 (Figure 3b; Table E14). Similarly, incident HF was associated with a two-fold

increase in 10-year mortality among COPD patients compared with those without incident HF (Figure 3c; Table

E14). The difference in mortality rates between patients with COPD-iHF diagnosed in 2006 compared to

patients with COPD without incident HF in 2006 was consistent over 10 years of follow-up (Figure 4).

Comparison of mortality rates COPD-iHF vs COPD-no HF stratified by severity of airflow

limitation

There was a non-significant trend towards higher 1-year, 5-year, and 10-year mortality in patients with COPD-

iHF with more severe airflow limitation (Figure 5a, 5b, and 5c). The overall 1-year, 5-year and 10-year

mortality rates of patients with COPD-iHF were significantly higher than the COPD-no HF patients, regardless

of severity of airflow limitation (Figure 5a, 5b and 5c; Table E15).

Temporal trends in the mortality rates of patients with COPD-iHF from 2006 to 2016

COPD-iHF patients in 2011 and 2015 experienced 1-year mortality rates that was no different from those

patients with COPD-iHF in 2006 (Figure 6a; E16). Similarly, the 5-year mortality rate among patients with

COPD-iHF in 2011 was no different than seen in patients with COPD-iHF in 2006 (Figure 6b; Table E16).

Causes of death

There was no difference in the proportion of deaths attributed to cardiovascular causes in patients with COPD-

iHF in 2011 vs patients with COPD-iHF in 2006 (42% vs 39%) (Figure 7). Approximately one third of all

deaths were attributed to COPD, regardless of whether a patient experienced incident HF or not (Table E17).

Among those with COPD-iHF, over 10 years of follow-up, the proportion of deaths attributed to cardiovascular

causes was not affected by severity of airflow limitation (33% GOLD1-2 vs 33% GOLD3-4; Figure 7).

Discussion

This study of a large, nationally representative population in the UK over one decade provides vital insights into

trends in the incidence of HF within the primary care COPD population. We also investigate the impact of

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incident HF on mortality among patients with COPD and how this has changed over time and with the severity

of airflow limitation.

The major findings of the study could be summarised as follows: 1) in the UK, the crude incidence of HF in the

COPD population was 1.18 per 100 persons years and this has remained steady over the past decade; 2) in

patients with COPD, the incidence of HF was much higher among men, the elderly, and those with severe

airflow limitation (GOLD3-4); 3) in patients with COPD, incident HF was associated with a greater than three-

fold increase in 1-year mortality and a two-fold increase in 5- and 10-year mortality compared with those who

did not develop HF; and 4) the effect of incident HF on the short- and long-term mortality of patients with

COPD did not improve over time, nor was it different in relation to severity of airflow limitation.

COPD and the risk of incident HF: mechanistic explanation

Previous studies have demonstrated an association between COPD and incident HF. A large population-based

study of patients in the community revealed a linear relationship between severity of airflow obstruction and

impaired left ventricular filling without significant changes in left ventricular ejection fraction (23). Our results

are similar to those of large community cohorts and registries where the incidence of HF was 1-1.5 per 100

person years at risk in patients with severe airflow limitation (4). There have been several potential explanations

for the increased risk of HF in patients with COPD. Firstly, multiple traditional risk factors are associated with

both COPD and HF; for instance, smoking, the most common cause of COPD (24), has been associated with a

50% increased risk of HF (25). Secondly, there is a high prevalence of subclinical cardiac dysfunction (23, 26)

and HF precursors (e.g., diabetes mellitus, atrial fibrillation, hypertension etc.) in patients with COPD (27).

Furthermore, patients with COPD and cardiovascular disease (e.g., ischemic heart disease, atrial fibrillation etc.)

are systemically under-prescribed cardiovascular medications including beta-blockers, statins, and aspirin (28),

which may hasten development of HF, especially in patients with antecedent subclinical cardiac dysfunction.

Thirdly, while COPD has been associated with an increased risk of both HF reduced ejection fraction and HF

preserved ejection fraction, there appears to be a differential predilection to HF preserved ejection fraction (4, 5,

29). This raises the role of comorbidity (COPD)-specific systemic inflammation in the development of HF

preserved ejection fraction (30, 31). The role of arterial hypoxemia due to lung disease has also been shown to

influence outcomes in patients with HF preserved ejection fraction (32). Finally, cor pulmonale and the effect of

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pulmonary hyperinflation on ventricular hemodynamics could be other plausible explanations for this

association (33).

Temporal trends in the incidence of HF in patients with COPD in the UK: stable incidence

or continued under recognition?

The crude incidence of HF in the COPD population was steady over time; meanwhile, the crude incidence of HF

in the general UK population is increasing (10). Crude incidence was higher in males, at older ages, in former

smokers, and in those with more severe airflow limitation (GOLD3-4). Higher crude incidence in former

smokers and in those with more severe airflow limitation may, at least in part, be attributed to age as older

persons are more likely to be former smokers than current smokers and have more severe disease than younger

persons. The stable incidence of HF in the past decade observed in our study could be a consequence of under

recognition and lack of improvement in the diagnosis of HF in patients with COPD. It has previously been

demonstrated that HF is often underdiagnosed in the COPD population (14, 15, 34, 35), despite patients with

COPD being at greater risk for developing HF and HF precursors, such as angina and myocardial infarction,

than people without COPD (27). There are a number of possible explanations for this under-recognition. Firstly,

HF and COPD share dyspnoea as a primary complaint, and determining the exact mechanism for dyspnoea is

difficult (36). Secondly, there is no single diagnostic test for HF (37, 38). In contrast to HFrEF, where the

diagnosis is reasonably straightforward, the diagnosis of HF preserved ejection fraction is cumbersome,

especially in patients presenting with dyspnoea and multiple co-morbidities. For diagnosing HF preserved

ejection fraction, dyspnoea and a normal left ventricular ejection fraction need to be coupled with additional

measures of left ventricular diastolic dysfunction (e.g. left ventricular hypertrophy, increased left atrial diameter,

tissue Doppler studies etc.), and plasma levels of natriuretic peptides (31, 37, 38). This diagnosis is even more

challenging in patients with COPD as the interpretation of echocardiogram is hindered by poor acoustic

windows and inadequate Doppler estimation in patients with a high residual lung volume (39, 40). Furthermore,

the diagnostic accuracy of natriuretic peptides is also limited in COPD, particularly in those with HF preserved

ejection fraction (41). As previous research has shown that HF is often under-diagnosed in the COPD

population and that patients with COPD experience higher risk for HF than the general population, the lack of a

similar trend in HF incidence in the COPD population as seen in the general population suggests that HF may

still be under-recognised.

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Impact of incident HF on mortality in COPD patients

In patients with COPD, incident HF was associated with a greater than three-fold increase in 1-year mortality

rate and a two-fold increase in 5-year and 10-year mortality rates. While the incidence of HF was higher in

patients with severe airflow limitation, the impact of incident HF on mortality was not modified by the degree of

airflow limitation. The effect of incident HF on the mortality of patients with COPD did not improve over time,

contrary to improved survival following incident HF in the general population (42, 43). The increased mortality

of patients with COPD-iHF could be related to HF; however, this may not be the only driver. Previous research

has shown that patients with COPD and concomitant HF experience greater numbers of additional concomitant

conditions, beyond COPD and HF, compared to patients with COPD without concomitant HF and that increased

levels of comorbidity result in greater mortality (44, 45). When it is recognised, diagnosis of HF in the COPD

population is often delayed, which may mean HF is more severe and the provision of treatment delayed (46),

negatively impacting survival. Additionally, it is well known that HF and other cardiovascular conditions are

under-treated in the COPD population, with patients with COPD less likely to be prescribed survival-modifying

cardiovascular medication than the general population (28). Our findings underscore the importance of

identification of HF in patients with COPD early in the course of the disease where initiation of disease-

modifying HF therapy, especially in HF reduced ejection fraction, may improve long term outcomes.

Causes of death and temporal trends in cardiovascular mortality among COPD-iHF

There no difference in cardiovascular mortality in patients with COPD-iHF over the study period. This contrasts

the trend seen in the wider COPD population towards decreasing cardiovascular deaths (47). Taylor et al. looked

at the causes of death in patients with HF from the general UK primary care population from 2000-2017 but did

not look at changes over time (42). Taylor et al. found that 55.7% of deaths of patients with HF were attributed

to cardiovascular causes (42), which is much more than the 36% of deaths attributed to cardiovascular causes in

the COPD-iHF population from 2011-2016 seen here. The difference does appear to be made up by a greater

proportion of deaths attributed to respiratory causes in the COPD-iHF population than in the wider HF

population (COPD-iHF [presented here] vs wider HF population (42): 39% vs 16%) as proportions of death

attributed to all other causes were similar in the two populations.

Increasing airflow limitation saw no change in the proportion of deaths attributed to cardiovascular causes in

patients with COPD-iHF. These trends are different to those seen in the wider COPD population, where deaths

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due to respiratory causes increase and deaths due to cardiovascular causes decrease with increasing airflow

limitation (48). This may represent the increased morbidity in our cohort due to HF comorbidity, potentially

shifting mortality patterns in patients with less severe airflow limitation towards trends seen in patients with

greater airflow limitation. Previously, Lawson et al. found the effect of COPD on mortality of patients with

incident HF increased with increasing airflow limitation compared to patients with incident HF without COPD

with a median follow-up of 2.6 years (49). When looking only at patients with incident HF with COPD, Lawson

et al. found significantly greater adjusted odds of mortality for patients with more severe airflow limitation

(GOLD3-4) compared with those with milder airflow limitation (GOLD1-2) (49). Here, we found increased

effect of HF on the mortality rate of patients with COPD with more severe airflow limitation in the short-term

(1-year), but the difference was not significant and attenuated when looking at longer-term mortality rates. The

cohort from Lawson et al. had a higher proportion of patients with severe-to-very-severe airflow limitation than

our cohort, which may also contribute to the differences (49).

Strengths and Limitations

A major strength of this study is the use of one of the largest longitudinal, nationally representative databases in

the world, CPRD (17), linked with mortality data from ONS that is nearly 100% complete (50). There is a

potential for misclassification of cause of death; however, in a review undertaken by ONS, the proposed and

confirmed underlying cause of death matched at ICD chapter level in 88% of cases and there was exact

agreement (to 4 digits) in 78% of cases, rising to 80% when records matching to 3 digits were included (51). A

potential limitation is the validity of case definitions within electronic health care records. We used a validated

case definition for COPD (18); however, although no validation of a case definition for HF has been undertaken

in CPRD we used Read codes reviewed by two cardiologists and two respiratory physicians. Another limitation

is that measurements of ejection fraction and biomarkers used to determine the severity or type of HF are not

available in CPRD data. As we cannot determine type of HF reliably, we are unable to determine if patients with

HF reduced ejection fraction are being managed according to guidelines.

Conclusions

The incidence of HF in the UK primary care COPD population in the last decade was steady, contrary to

increasing incidence of HF seen in the general population of the UK (10). Patients with COPD-iHF experienced

a significantly higher mortality than patients with COPD-no HF. The mortality rates in England of patients with

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COPD-iHF have not improved over the last decade, indicating that patients with COPD-iHF have not seen the

same increases in survival previously seen in the general population with incident HF (42, 43). This survival

differential may be explained by previous research showing that patients with COPD and cardiovascular

conditions are often under-managed compared to the general population (28). Our results, coupled with previous

research, suggest that HF remains under-diagnosed in the COPD population and that, when recognised, may be

under-treated resulting in poorer survival. Bespoke clinical guidelines for the diagnosis and management of HF

in the presence of COPD, and implementation tools with audit to support quality improvement, are needed in

order to improve diagnosis and outcome.

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References

1. Cowie MR, Anker SD, Cleland JGF, Felker GM, Filippatos G, Jaarsma T, et al. Improving care for

patients with acute heart failure: before, during and after hospitalization. ESC Heart Fail. 2014;1(2):110-45.

Epub 2014/12/01. doi: 10.1002/ehf2.12021. PubMed PMID: 28834628.

2. Rusinaru D, Saaidi I, Godard S, Mahjoub H, Battle C, Tribouilloy C. Impact of chronic obstructive

pulmonary disease on long-term outcome of patients hospitalized for heart failure. Am J Cardiol.

2008;101(3):353-8. Epub 2008/02/02. doi: 10.1016/j.amjcard.2007.08.046. PubMed PMID: 18237599.

3. The Academy of Medical Sciences. Multimorbidity: a priority for global health research. 2018.

4. Agarwal SK, Heiss G, Barr RG, Chang PP, Loehr LR, Chambless LE, et al. Airflow obstruction, lung

function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study. Eur J Heart

Fail. 2012;14(4):414-22. Epub 2012/03/01. doi: 10.1093/eurjhf/hfs016. PubMed PMID: 22366234; PubMed

Central PMCID: PMCPMC3530346.

5. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac

comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved

versus reduced ejection fraction. J Am Coll Cardiol. 2012;59(11):998-1005. Epub 2012/03/10. doi:

10.1016/j.jacc.2011.11.040. PubMed PMID: 22402071; PubMed Central PMCID: PMCPMC4687406.

6. Chen W, Thomas J, Sadatsafavi M, FitzGerald JM. Risk of cardiovascular comorbidity in patients with

chronic obstructive pulmonary disease: a systematic review and meta-analysis. The Lancet Respiratory

Medicine. 2015;3(8):631-9. doi: 10.1016/s2213-2600(15)00241-6.

7. de Miguel Diez J, Chancafe Morgan J, Jimenez Garcia R. The association between COPD and heart

failure risk: a review. Int J Chron Obstruct Pulmon Dis. 2013;8:305-12. Epub 2013/07/13. doi:

10.2147/COPD.S31236. PubMed PMID: 23847414; PubMed Central PMCID: PMCPMC3700784.

8. Guder G, Rutten FH. Comorbidity of heart failure and chronic obstructive pulmonary disease: more

than coincidence. Curr Heart Fail Rep. 2014;11(3):337-46. Epub 2014/07/02. doi: 10.1007/s11897-014-0212-x.

PubMed PMID: 24980212.

9. Hannink JD, van Helvoort HA, Dekhuijzen PN, Heijdra YF. Heart failure and COPD: partners in

crime? Respirology. 2010;15(6):895-901. Epub 2010/06/16. doi: 10.1111/j.1440-1843.2010.01776.x. PubMed

PMID: 20546188.

15

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

396


10. Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, et al. Temporal trends and patterns

in heart failure incidence: a population-based study of 4 million individuals. The Lancet. 2017;391(10120):572-

80. doi: 10.1016/s0140-6736(17)32520-5.

11. British Lung Foundation. The Battle for Breath- The Impact of Lung Disease in the UK. British Lung

Foundation, 2016.

12. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ. Heart failure and chronic

obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail. 2009;11(2):130-9. Epub

2009/01/27. doi: 10.1093/eurjhf/hfn013. PubMed PMID: 19168510; PubMed Central PMCID:

PMCPMC2639415.

13. Rutten FH. Diagnosis and mangement of heart failure in COPD. In: Rabe KF, Wedzicha JA, Wouters

EF, editors. Eur Respir Monogr. COPD and comorbidity. 592013. p. 50-63.

14. Rutten FH, Cramer MJ, Lammers JW, Grobbee DE, Hoes AW. Heart failure and chronic obstructive

pulmonary disease: An ignored combination? Eur J Heart Fail. 2006;8(7):706-11. Epub 2006/03/15. doi:

10.1016/j.ejheart.2006.01.010. PubMed PMID: 16531114.

15. Boudestein LC, Rutten FH, Cramer MJ, Lammers JW, Hoes AW. The impact of concurrent heart

failure on prognosis in patients with chronic obstructive pulmonary disease. Eur J Heart Fail. 2009;11(12):1182-

8. Epub 2009/11/06. doi: 10.1093/eurjhf/hfp148. PubMed PMID: 19887495.

16. Plachi F, Balzan FM, Sanseverino RA, Palombini DV, Marques RD, Clausell NO, et al. Characteristics

associated with mortality in patients with chronic obstructive pulmonary disease (COPD)-heart failure

coexistence. Prim Health Care Res Dev. 2018:1-5. Epub 2018/02/22. doi: 10.1017/S1463423618000117.


17. Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, et al. Data Resource Profile:

Clinical Practice Research Datalink (CPRD). Int J Epidemiol. 2015;44(3):827-36. Epub 2015/06/08. doi:

10.1093/ije/dyv098. PubMed PMID: 26050254; PubMed Central PMCID: PMCPMC4521131.

18. Quint JK, Mullerova H, DiSantostefano RL, Forbes H, Eaton S, Hurst JR, et al. Validation of chronic

obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD). BMJ Open.

2014;4(7):e005540. Epub 2014/07/25. doi: 10.1136/bmjopen-2014-005540. PubMed PMID: 25056980;

PubMed Central PMCID: PMCPMC4120321.

19. National Institute for Health and Care Excellence (NICE). Chronic obstructive pulmonary disease in

over 16s: diagnosis and management. 2018.

16

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426


20. GOLD. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for

Chronic Obstructive Lung Disease (GOLD) 2017 [Webpage]. 2017 [10 Jan 2018]. Available from:

http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/.

21. Rothnie KJ, Chandan JS, Goss HG, Mullerova H, Quint JK. Validity and interpretation of spirometric

recordings to diagnose COPD in UK primary care. Int J Chron Obstruct Pulmon Dis. 2017;12:1663-8. Epub

2017/06/28. doi: 10.2147/COPD.S133891. PubMed PMID: 28652719; PubMed Central PMCID:

PMCPMC5473480.

22. Devis T, Rooney C. Death certification and the epidemiologist. Health Statistics Quarterly. 1999;1(21-

33).

23. Graham Barr R, Bluemke DA, Ahmed FS, Jeffery Carr J, Enright P, Hoffman E, et al. Percent

emphysema, airflow obstruction, and impair left ventricular filling. The New England Journal of Medicine.

2010;362:217-27.

24. Mannino DM, Watt G, Hole D, Gillis C, Hart C, McConnachie A, et al. The natural history of chronic

obstructive pulmonary disease. Eur Respir J. 2006;27(3):627-43. Epub 2006/03/02. doi:

10.1183/09031936.06.00024605. PubMed PMID: 16507865.

25. Suskin N, Sheth T, Negassa A, Yusuf S. Relationship of current and past smoking to mortality and

morbidity in patients with left ventricular dysfunction. Journal of the American College of Cardiology.

2001;37(6):1677-82. doi: 10.1016/s0735-1097(01)01195-0.

26. Lam CS, Lyass A, Kraigher-Krainer E, Massaro JM, Lee DS, Ho JE, et al. Cardiac dysfunction and

noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the

community. Circulation. 2011;124(1):24-30. Epub 2011/06/15. doi: 10.1161/CIRCULATIONAHA.110.979203.

PubMed PMID: 21670229; PubMed Central PMCID: PMCPMC3257876.

27. Morgan AD, Rothnie KJ, Bhaskaran K, Smeeth L, Quint J. Chronic obstructive pulmonary disease and

the risk of 12 cardiovascular diseases: a population-based study using UK primary care data. Thorax.

2018;73:877–9.

28. Rasmussen D, Bodtger U, Lamberts M, Lange P, Jensen M. Beta-blocker, aspirin and statin usage after

myocardial infarction in patients with and without COPD. A nationwide analysis from 1995 to 2015 in

Denmark. European Respiratory Journal. 2018;52(Suppl 62):1933.

29. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC, Committee ASA, et al. Clinical

presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart

17

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

http://goldcopd.org/gold-2017-global-strategy-diagnosis-management-prevention-copd/


failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry

(ADHERE) Database. J Am Coll Cardiol. 2006;47(1):76-84. Epub 2006/01/03. doi: 10.1016/j.jacc.2005.09.022.


30. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction:

comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial

inflammation. J Am Coll Cardiol. 2013;62(4):263-71. Epub 2013/05/21. doi: 10.1016/j.jacc.2013.02.092.


31. Redfield MM. Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2016;375(19):1868-77.

Epub 2016/12/14. doi: 10.1056/NEJMcp1511175. PubMed PMID: 27959663.

32. Andrea R, Lopez-Giraldo A, Falces C, Lopez T, Sanchis L, Gistau C, et al. Pulmonary function

predicts mortality and hospitalizations in outpatients with heart failure and preserved ejection fraction. Respir

Med. 2018;134:124-9. Epub 2018/02/08. doi: 10.1016/j.rmed.2017.12.004. PubMed PMID: 29413499.

33. Shujaat A, Minkin R, Eden E. Pulmonary hypertension and chronic cor pulmonale in COPD.

International Journal of COPD. 2007;2(3):273-82.

34. McCullough P, Hollander JE, Nowak R, Storrow AB, Duc P, Omland T, et al. Uncovering Heart

Failure in Patients with a History of Pulmonary Disease: Rationale for the Early UseofB-typeNatriuretic Peptide

in the Emergency Department. Acad Emerg Med. 2003;10(3):198-204.

35. Rutten FH, Cramer MJ, Grobbee DE, Sachs AP, Kirkels JH, Lammers JW, et al. Unrecognized heart

failure in elderly patients with stable chronic obstructive pulmonary disease. Eur Heart J. 2005;26(18):1887-94.

Epub 2005/04/30. doi: 10.1093/eurheartj/ehi291. PubMed PMID: 15860516.

36. Beghe B, Verduri A, Roca M, Fabbri L. Exacerbation of respiratory symptoms in COPD patients may

not be exacerbations of COPD. Eur Respir J. 2013;41(4):993-5. Epub 2013/04/02.

37. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for

the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of

acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special

contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891-975. Epub

2016/05/22. doi: 10.1002/ejhf.592. PubMed PMID: 27207191.

38. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA

guideline for the management of heart failure: a report of the American College of Cardiology

18

457

458

459

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463

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465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485


Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-

327. Epub 2013/06/07. doi: 10.1161/CIR.0b013e31829e8776. PubMed PMID: 23741058.

39. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, et al.

Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir

Crit Care Med. 2003;167(5):735-40. Epub 2002/12/14. doi: 10.1164/rccm.200210-1130OC. PubMed PMID:

12480614.

40. Warnier MJ, Rutten FH, Numans ME, Kors JA, Tan HL, de Boer A, et al. Electrocardiographic

characteristics of patients with chronic obstructive pulmonary disease. COPD. 2013;10(1):62-71. Epub

2013/02/19. doi: 10.3109/15412555.2012.727918. PubMed PMID: 23413894.

41. Hawkins NM, Khosla A, Virani SA, McMurray JJ, FitzGerald JM. B-type natriuretic peptides in

chronic obstructive pulmonary disease: a systematic review. BMC Pulm Med. 2017;17(1):11. Epub 2017/01/12.

doi: 10.1186/s12890-016-0345-7. PubMed PMID: 28073350; PubMed Central PMCID: PMCPMC5223538.

42. Taylor CJ, Ordonez-Mena JM, Roalfe AK, Lay-Flurrie S, Jones NR, Marshall T, et al. Trends in

survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study.

BMJ. 2019;364:l223. Epub 2019/02/15. doi: 10.1136/bmj.l223. PubMed PMID: 30760447.

43. Lawson CA, Zaccardi F, Squire I, Ling S, Davies MJ, Lam CSP, et al. 20-year trends in cause-specific

heart failure outcomes by sex, socioeconomic status, and place of diagnosis: a population-based study. The

Lancet Public Health. 2019;4(8):e406-e20. doi: 10.1016/s2468-2667(19)30108-2.

44. Kaszuba E, Odeberg H, Rastam L, Halling A. Heart failure and levels of other comorbidities in patients

with chronic obstructive pulmonary disease in a Swedish population: a register-based study. BMC Res Notes.

2016;9:215. Epub 2016/04/14. doi: 10.1186/s13104-016-2008-4. PubMed PMID: 27067412; PubMed Central

PMCID: PMCPMC4828898.

45. Kaszuba E, Odeberg H, Rastam L, Halling A. Impact of heart failure and other comorbidities on

mortality in patients with chronic obstructive pulmonary disease: a register-based, prospective cohort study.

BMC Fam Pract. 2018;19(1):178. Epub 2018/11/27. doi: 10.1186/s12875-018-0865-8. PubMed PMID:

30474547; PubMed Central PMCID: PMCPMC6260666.

46. Hayhoe B, Kim D, Aylin PP, Majeed FA, Cowie MR, Bottle A. Adherence to guidelines in

management of symptoms suggestive of heart failure in primary care. Heart. 2019;105(9):678-85. Epub

2018/12/06. doi: 10.1136/heartjnl-2018-313971. PubMed PMID: 30514731.

19

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508

509

510

511

512

513

514


47. Gayle AV, Axson EL, Bloom CI, Navaratnam V, Quint JK. Changing causes of death for patients with

chronic respiratory disease in England, 2005-2015. Thorax. 2019. Epub 2019/01/31. doi: 10.1136/thoraxjnl-

2018-212514. PubMed PMID: 30696745.

48. Alfageme I, Reyes N, Merino M, Reina A, Gallego J, Lima J, et al. The effect of airflow limitation on

the cause of death in patients with COPD. Chron Respir Dis. 2010;7(3):135-45. Epub 2010/08/07. doi:

10.1177/1479972310368692. PubMed PMID: 20688891.

49. Lawson CA, Mamas MA, Jones PW, Teece L, McCann G, Khunti K, et al. Association of Medication

Intensity and Stages of Airflow Limitation With the Risk of Hospitalization or Death in Patients With Heart

Failure and Chronic Obstructive Pulmonary Disease. JAMA Netw Open. 2018;1(8):e185489. Epub 2019/01/16.

doi: 10.1001/jamanetworkopen.2018.5489. PubMed PMID: 30646293; PubMed Central PMCID:

PMCPMC6324325.

50. Wells C. Impact of the Implementation of IRIS Software for ICD-10 Cause of Death Coding on

Mortality Statistics, England and Wales. Office of National Statistics (ONS); 2014.

51. Death Certification Reform: A Case Study on the Potential Impact on Mortality Statistics, England and

Wales. In: (ONS) OoNS, editor. 2012.

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Figure Legends

Figure 1. Defining the study population from the Clinical Practice Research Datalink (CPRD). Chronic obstructive pulmonary

disease (COPD). Heart failure (HF).

Figure 2. Crude incidence of heart failure (HF) in the chronic obstructive pulmonary disease (COPD) population, 2006-2016.

Incidence per 100 person-years. 95% confidence intervals shown.

Figure 3. Adjusted mortality rate ratios (aMRR) with 95% confidence intervals comparing the a) 1-year, b) 5-year, and c) 10-

year mortality of patients with chronic obstructive pulmonary disease (COPD) and incident heart failure (HF) in 2006, 2011,

and 2015 with the 1-year, 5-year, and 10-year mortality of patients with COPD without incident HF in 2006, 2011, and

2015, respectively. Estimates from Poisson regression adjusted for age, sex, body mass index, severity of airflow limitation,

smoking status, history of cardiovascular disease, and diabetes.

Figure 4. Kaplan-Meier survivor curve with 95% confidence intervals (CI) comparing patients with chronic obstructive

pulmonary disease (COPD) with (hf_2006 = 1) and without (hf_2006 = 0) incident heart failure (HF) in 2006 over 10 years of

follow-up.

Figure 5. Adjusted mortality rate ratios (aMRR) with 95% confidence intervals comparing the 1-year, 5-year, and 10-year

mortality of patients with COPD and incident HF in 2006 with the mortality of patients with COPD without incident HF in

2006 stratified by severity of airflow limitation. Global Initiative for Chronic Obstructive Lung Diseases (GOLD) staging of

COPD severity (20) where GOLD1-2 is mild-to-moderate airflow limitation and GOLD3-4 is severe-to-very severe airflow

limitation. Estimates from Poisson regression adjusted for age, sex, body mass index, smoking status, history of

cardiovascular disease, and diabetes.

Figure 6. Adjusted mortality rate ratios (aMRR) with 95% confidence intervals comparing the 1-year and 5-year mortality of

patients with chronic obstructive pulmonary disease (COPD) with incident heart failure (HF) in 2011 and 2015 with the

mortality of patients with COPD with incident HF in 2006. Estimates from Poisson regression adjusted for age, sex, body

mass index, severity of airflow limitation, smoking status, history of cardiovascular disease, and diabetes.

Figure 7. The proportion of deaths attributed to respiratory (J), circulatory (I), neoplasm (C, D00-D49), and all other causes

for patients with chronic obstructive pulmonary disease (COPD) with incident heart failure (HF) in (A) 2006 and (B) 2011

over five years of follow-up and for patients with COPD with incident HF in 2006 over ten years of follow-up stratified by

severity of airflow limitation (C) mild-to-moderate airflow limitation (GOLD1-2) and (D) severe-to-very severe airflow

limitation (GOLD3-4). Chapters defined according to the International Statistical Classification of Diseases and Related

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Health Problems 10th Revision (ICD-10). Global Initiative for Chronic Obstructive Lung Diseases (GOLD) staging of COPD

severity (20).

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Tables

Incident HF

n (%)No Incident HF

n (%) Number of Patients (N) 4,862 91,125 % of patients with COPD 5.1 94.9 Female 1,733 (35.6) 40,606 (44.6) Age at COPD Diagnosis, yearsMedian (interquartile range) 68.8 (61.2, 75.9) 64.5 (56.9, 72.3)

Age at HF Diagnosis, yearsMedian (interquartile range) 75.9 (69.0, 81.8) ~

Smoking Status Current Smoker 1,660 (34.1) 41,325 (45.4) Former Smoker 3,202 (65.9) 49,800 (54.6) Body Mass Index Underweight (< 18.5) 166 (3.4) 4,923 (5.4) Healthy Weight (18.5-24.9) 1,461 (30.1) 33,728 (37.0) Overweight (25.0-29.9) 1,655 (34.0) 29,454 (32.3) Obese (>= 30) 1,512 (31.1) 21,518 (23.6) Missing Data 68 (1.40) 1,502 (1.7)

GOLD Stage 1: Mild 1,527 (31.4) 32,761 (36.0) 2: Moderate 1,819 (37.4) 36,241 (39.8) 3: Severe 1,231 (25.3) 18,108 (19.8) 4: Very Severe 285 (5.9) 4,015 (4.4)

HF Risk Factors* Atrial Fibrillation 659 (13.6) 4,201 (4.6) Diabetes 769 (15.8) 9,030 (9.9) Hypertension 2,345 (48.2) 43,463 (47.7) Ischaemic Heart Disease 1,499 (30.8) 13,162 (14.4) Peripheral Artery Disease 493 (10.1) 5,371 (5.9) Stroke 411 (8.5) 5,089 (5.6)

Table 1. Descriptive statistics.Presented for patients with chronic obstructive pulmonary disease (COPD) with incident heart failure (HF) during the study period and those without incident HF during the study period. Interquartile range (IQR). Global Initiative for Chronic Obstructive Lung Diseases (GOLD) staging of COPD severity (20). *Recorded at start of follow-up; patients could have multiple risk factors.

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