Natural history of COPD exacerbations in a general practice based COPD population

Running title: Natural history AECOPD

Authors: Kieran J Rothnie1,2, Hana Müllerová3, Liam Smeeth2, Jennifer K Quint1,2

Affiliations

1. Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London

2. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London

3. Respiratory Epidemiology, GlaxoSmithKline R&D, Uxbridge

Corresponding author Kieran J RothnieRespiratory Epidemiology, Occupational Medicine and Public HealthNational Heart and Lung InstituteEmmanuel Kaye BuildingImperial College LondonLondonSW3 6LR

Email: k.rothnie@imperial.ac.uk

Tel: +44 20 7594 8824

Author contributions: conceived of and designed the study: KJR, HM, JKQ; obtained and managed data: KJR; analysed the data: KJR; interpreted data: KJR, HM, LS, JKQ; wrote the first draft: KJR; edited the paper for important intellectual content: KJR, HM, LS, JKQ.

Subject: 9.6 COPD: Epidemiology

Word count: 3492

This article has an online data supplement, which is accessible from this issue's table of content online at www.atsjournals.org

At a glance commentary

Scientific Knowledge on the SubjectPeople who have frequent exacerbations are known to have increased mortality compared to infrequent exacerbators, and severe exacerbations (requiring hospitalisation) are associated with a higher risk of death than those managed in the community. However, the impact of multiple moderate exacerbations (those managed outside hospital) on the natural history of COPD is unknown. Recent evidence has suggested that there is substantial short term variation in year-to-year AECOPD rates. What This Study Adds to the FieldWe carried out a large study to investigate the natural history of COPD exacerbations with a follow-up of up to 10 years. Compared to previous studies, our study is larger in terms of patient numbers, has longer follow-up and, importantly, is generalizable to real life COPD population seen in clinical practice. We demonstrate that when taken as a cross-section of all COPD patients – a substantial proportion do not seem to exacerbate, however in our generalizable population, this proportion was half the size than previously estimated. In addition, we also show that most patients do in fact exacerbate at least once following diagnosis of COPD, but once their COPD is established, many do not exacerbate again over the 10 years of follow-up (mean 4.9 years), suggesting phenotypic complexity among the COPD population. Although there is likely to be substantial year-to-year variation in exacerbation rates, due to our long follow-up, we were able to demonstrate that exacerbation frequency in a single year does predict long term exacerbation rates in a graduated fashion. We also found a graduated increase in risk of mortality associated with moderate exacerbations (from 0-5+ per year). However no frequency of moderate exacerbations exceeded the mortality risk from a severe exacerbation.

Abstract

Rationale

Acute exacerbations (AECOPD) are important adverse events in the natural history of COPD.

Objectives

To investigate the natural history of AECOPD over 10-years of follow-up.

Methods and Results

We identified 99,574 patients with COPD 01/Jan/04-31/March/15 from the UK Clinical Practice Research Datalink. We defined moderate AECOPD as those managed outside hospital and severe as those requiring hospitalisation. During the baseline period (first year of follow-up), patients were grouped according to the number and severity of AECOPD and then followed for a maximum of 10 years (mean 4.9 years). We investigated the effect of baseline AECOPD number and severity on risk of further events and death.

Around one-quarter of the COPD patients did not exacerbate during follow-up. Compared to no AECOPD in the baseline period, AECOPD number predicted the future long-term rate of AECOPD in a graduated fashion, ranging from HR 1.71(1.66-1.77) for one to HR 3.41(3.27-3.56) for 5+ events. Two or more moderate AECOPD were also associated with an increased risk of death in a graduated fashion, ranging from HR 1.10(1.03-1.18) for 2 moderate AECOPD to HR 1.57(1.45-1.70) for 5+ moderate AECOPD, compared to those with no AECOPD at baseline. Severe AECOPD were associated with an even higher risk of death (HR 1.79,1.65-1.94).

Conclusions

A large proportion of COPD patients do not exacerbate over a maximum 10 years of follow-up. AECOPD frequency in a single year predicts long-term AECOPD rate. Increasing frequency and severity of AECOPD is associated with risk of death, and highlights the importance of preventing AECOPD.

Introduction

Acute exacerbations of COPD (AECOPD) are important events in the natural history of the disease. People who have frequent exacerbations (2+/year) have higher mortality, worse quality of life, and faster FEV1 decline than those with infrequent exacerbations 0-1/year(1). Increasing exacerbation frequency is known to be a risk factor for future exacerbation events(2), and is thought to be a stable trait(2, 3), with exacerbations clustering in time(4). Previous work has shown that increased frequency of moderate AECOPD are associated with an increased risk of death in the year following an AECOPD(5) and that a hospitalisation for AECOPD (i.e. severe AECOPD) is associated with an increased risk of death, with the risk of death increasing with increasing frequency of severe AECOPD(6).

Most published studies split patients with COPD into infrequent (0-1 events/years) and frequent (2+ events/year) AECOPD categories due to the understanding of the importance of the frequent exacerbator phenotype. It is unclear, however, how a graduated increase in moderate AECOPD (managed outside hospital) events impacts on the risk of death, and how the frequency of moderate events compares to hospitalised events in terms of risk of death. Furthermore, previous studies of the natural history and impact of AECOPD frequency and severity, have made use of more severe cohorts, or those treated in secondary care and with a relatively short follow-up of up to three years (3, 4, 6-8). As most COPD patients are cared for in primary care, it is unclear if previous work can be generalised.

Using a representative population based cohort of linked primary care, hospitalization and mortality data, we investigated the effect of frequency and severity of AECOPD at baseline on the risk of: 1) death; and 2) future AECOPD. We also aimed to determine if more distant AECOPD have an effect on risk of death independent of the frequency of more recent events.

Some of the results of these studies have been previously reported in the form of an abstract (9).

Methods

Data source and study population

We used data from the Clinical Practice Research Datalink (CPRD) linked with Hospital Episodes Statistics (HES) data and Office of National Statistics (ONS) mortality database.

We used our previously validated algorithm to identify patients with COPD in the CPRD(10). Briefly, this consisted of patients aged over 35; with a record for a validated diagnostic code for COPD; and a smoking history. We included all patients in the CPRD with COPD if they were eligible for linkage with HES, ONS and deprivation data (index of multiple deprivation [IMD](11)), and had at least one year between joining the database and censoring at death or moving outside the system. The Read codes used to identify COPD are presented in the appendix (Table S1, appendix).

We used our previously validated algorithms to identify both moderate(12) and severe AECOPD(13). Further details on the data source and covariate and outcomes ascertainment are in the supplementary material.

Statistical analysis

Cohort study

This was an open cohort study using data from 1 January 2004-31 March 2015 (figure S1-S3, appendix). During the study period, patients were eligible to begin follow-up after both diagnosis with COPD and entry into the CPRD database. Patients who entered the CPRD database and who already had a diagnosis of COPD were labelled as having “established disease”, and those who developed COPD during their time in the CPRD database were labelled as “incident disease”.

The exposure categories were: 0, 1, 2, 3, 4, and 5+ moderate AECOPD (and no severe AECOPD); and 1+ severe AECOPD (and any number of moderate AECOPD). Patients were categorised into these categorises during their first year of available data post-COPD diagnosis, hereafter called the “baseline period”. Outcomes were then ascertained during follow-up period starting from the end of the baseline period, up to a maximum available follow up of ten years and two months.

Initially we described the rates of subsequent moderate and severe AECOPD and time to first AECOPD by exposure category. We then used Cox proportional hazards models to investigate the effect of baseline AECOPD frequency and severity on time to first moderate AECOPD and severe AECOPD in separate analyses, adjusted for possible confounders. Covariates were identified in the period before study follow up start. Depression, anxiety, GORD, and asthma were ascertained in the baseline year only (i.e. in the same year as AECOPD frequency categorisation). All other

comorbidities (MI, stroke, heart failure, bronchiectasis, and lung cancer) were ascertained at any time before start of follow-up. mMRC score was ascertained in the baseline year, and GOLD grade of airflow limitation and BMI were ascertained using the closest measurement before start of follow-up. We then extended these models using the Andersen-Gill method to allow for repeat outcomes (AECOPD) within person. Andersen-Gill models are an extension to Cox modelling, which allow for repeat events and preserve the ordering of events, and a robust sandwich covariance matrix for the estimates, this uses a jacknife estimate to provide robust standard errors.(14). We repeated each analysis stratified by timing of COPD diagnosis (established or incident COPD). We then investigated time to death by baseline AECOPD frequency and severity using Cox proportional hazards models.

In order to assess the impact of potential misclassification of AECOPD frequency in the first year, we also performed a sensitivity analysis which used the first two years of follow up to classify patients according to AECOPD frequency and severity. In this analysis, we categorised those who had no AECOPD in either of the first two years as having 0 moderate AECOPD, and then followed these patients up for up to nine years.

Case-control study

We then conducted a nested case-control study for two of the outcomes (severe AECOPD, and death). Cases were matched to three controls based on age (year of birth) and GP practice at the time of the event. We used incidence density sampling to mimic time to event analysis, this meant that controls could become future cases(15). Odds ratios (ORs) produced by this method estimate the hazard ratio. For the case-control studies, events were ascertained between March 2012 and March 2015 for risk of death, and from March 2014 to March 2015 for risk of severe AECOPD. Covariates for the case-control study were ascertained at the start of the base cohort for the relevant case-control study.

The purpose of the case-control studies was to: 1) account for the potential survivor bias in the cohort study where patients needed to survive for at least one year to be categorised, potentially impacting on patients with a severe AECOPD who are at high risk of death; 2) to account for the time-varying nature of the AECOPD exposure and changes over time in the effect of the exposure; and 3) to investigate the effect of recent versus distant AECOPD on risk of future AECOPD and death.

We investigated frequency and severity of AECOPD in the previous three years separately (i.e. for 0-12 months before the event, 12-24 months before the event, and for 24-26 months before the event).

We used conditional logistic regression analysis, adjusting for the same confounders as the cohort study. We also additionally adjusted for number and severity of AECOPD at other time points to

assess whether more distant AECOPD continue to influence the outcomes, conditional on more recent AECOPD frequency and severity.

Post-hoc analysis

As a post-hoc analysis we investigated: 1) the proportion of patients who switched AECOPD frequency (both between frequent and infrequent AECOPD status, and any and zero AECOPD per year) by baseline AECOPD number and incident/established COPD; 2) the proportion of patients in each AECOPD frequency in both incident COPD groups and established COPD groups; and 3) whether receiving a prescription for a new inhaler was associated with switching from exacerbating in the baseline period to having no exacerbations in the first year of follow-up.

Analysis was conducted using Stata 14.2 MP.

Ethical approval

The protocol for this research was approved by the Independent Scientific Advisory Committee (ISAC) for MHRA Database Research (protocol number 17_013R) and the approved protocol was 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

In total, we included 99574 patients who survived at least one year during follow up (appendix, figure S4). The characteristics of included patients are displayed in Table 1 (and detailed further in Table S2 appendix). The median age was 68 (IQR, 60-76), 52% were current smokers, 24% of patients had GOLD grade 1 airflow limitation, 44% had grade 2, 26% had grade 3, and 6% had grade 4. In terms of frequency and severity of AECOPD in the first year, 51.8% had no AECOPD in the first year, 19.5% had one moderate AECOPD, 10.4% had two moderate AECOPD, 5.7% had three moderate AECOPD, 3.1% had four moderate AECOPD, and 5.1% had five or more moderate AECOPD, 4.3% had one or more severe AECOPD. Greater AECOPD frequency was associated with female sex, older age, ex-smokers, higher mMRC score, more severe airflow limitation, previous MI, stroke, heart failure, asthma, bronchiectasis, lung cancer, GORD, depression, and anxiety (test for trend, all p<0.001). Increasing AECOPD frequency was also associated with both under- and over-weight BMI (p<0.001).

38178 (38.3%) of patients had COPD diagnosed during the study (incident COPD), and 61396 (61.7%) had COPD at the start of their follow up (established COPD). Patients with incident disease were

more likely to have experienced an exacerbation during the baseline year (53.1% in patients with incident disease, compared to 42.4% in the established disease group). In terms of other risk factors, patients in the incident disease group had better lung function and lower mMRC scores (Table S3 appendix).

Cohort study

The mean follow up was 4.9 years (SD, 3.2 years). Over the follow-up, 26987 patients (26.4%) did not have any AECOPD in either the first year or during the follow-up period, meaning that only 47.7% of those with no AECOPD in the first year exacerbated at all over follow-up (Figure S5, appendix). Kaplan-Meier curves stratified by established and incident COPD indicated that almost all COPD patients with incident disease exacerbated at least once, this was also the case for those with established disease and at least one baseline exacerbation, however only around one quarter of those with established disease and no baseline exacerbations exacerbated over the follow-up (Figures 1-2). The rate of future and moderate and severe AECOPD increased with increasing baseline frequency of AECOPD in a graded fashion across all GOLD grades of airflow limitation (appendix, table S4). COPD patients had an average of 1.3 AECOPD per patient per year during the study period. From those with no AECOPD at baseline and survived over 10 years of follow up (N=5,623), 4,065 (72.3%) did not exacerbate at all.

When we performed our sensitivity analysis which categorised patients over the first 2 years of follow up, 77623 patients remained, of these 34246 (44.1%) had no event in either year, 22709 (29.3%) had no event during their entire follow-up.

Risk of Moderate AECOPD

In the analysis allowing for repeat moderate events, there was a graduated increase in the rate of moderate AECOPD by increasing frequency of baseline moderate AECOPD (Table 2). This pattern was maintained after adjustment for potential confounders, with the relative risk of further moderate AECOPD increasing from HR 1.71 (95% CI, 1.66-1.77) for those with one baseline moderate AECOPD to HR 5.50 (5.32-5.68) for those with five or more baseline moderate AECOPD, compared to those with no AECOPD at baseline. The effect of baseline AECOPD frequency and severity on risk of future moderate AECOPD were comparable between those with established and incident COPD and for time to first event analyses (appendix table S5-S6).

Risk of Severe AECOPD

Risk of future severe AECOPD behaved in a similar way to the risk of future moderate events (Table 3): There was again a graduated increase in the rate of severe AECOPD with increasing number of baseline moderate AECOPD, rising from 0.10 to 0.33 events per person year for those without vs.(0.32-0.35) five or more moderate AECOPD. The rate of severe AECOPD for those with one or more

baseline severe AECOPD was 0.51 per person year. This relationship corresponded with observed adjusted risk . Nevertheless, the presence of one or more baseline severe AECOPD was associated with the highest risk of future severe AECOPD (HR 3.65, 3.53-3.78). The effect of baseline AECOPD frequency and severity on risk of future severe AECOPD were comparable between those with established and incident COPD and for time to first event analyses (Appendix Table S7-S8).

Risk of Death

Risk of death again gradually increased with increasing frequency of moderate baseline AECOPD, and those who had one or more severe baseline AECOPD had the highest risk of death with HR 1.79 (95% CI 1.65-1.94) (Figure 3, Table 2).

Case control study – Odds of Death

We identified 7137 cases (deaths) and matched with three controls. Adjusted model considering 12 months period prior to death showed an increasing frequency of moderate AECOPD associated with higher risk of death up to over a doubling of risk of death for those with five or more moderate AECOPD. Patients with only one moderate AECOPD were not in an increased risk as compared to those without AECOPD (Table 2). Those who had a severe AECOPD in the previous 12 months had over a 14 times increased risk of death compared to those who had no AECOPD (OR 14.16 95% CI 9.45-21.2). Using alternative time periods of 12-24 and 24-36 months, we observed similar results for moderate AECOPD. However, the effect of severe AECOPD in the 12-24 and 24-36 months previously was attenuated. After adjusting for the frequency and severity of AECOPD at other time points, only frequency and severity of AECOPD in the previous 12 months remained associated with risk of death, with the exception of severe AECOPD in the 12-24 months (Table S10, appendix). Results of the severe AECOPD case control study are presented in the supplementary material (Table S11, appendix).

Post-hoc analysis

We found that 27.4% of patients without baseline AECOPD exacerbated in the first year, 40% of patients with one or more baseline AECOPD switched to none in the first year of follow-up, and 27% of patients with two or more AECOPD switched to none in the first year of follow-up. Compared to those with established disease, patients with incident COPD were more likely to switch from having no exacerbations at baseline to having one or more in the first year of follow up, and were more likely to switch from being an infrequent (0-1 AECOPD/year) to frequent exacerbator (2 or more AECOPD/year) (Table S12, appendix).

When comparing those with incident disease with a subset of those with established disease defined as less than five year’s duration, we found that the proportions of patients in each AECOPD

frequency group were very similar between incident and established disease after year 3 of follow-up (figure S8, appendix).

We found that having a prescription for a new class of inhaled therapy was associated with switching from being an exacerbator in the baseline period to having no exacerbations in the first year of follow-up (full details in appendix).

Discussion

In our population based study of patients with COPD with up to 10 years of follow-up (mean 4.9 years), we have identified a large sub-group of COPD patients (26%) who do not exacerbate. Among those who did experience an exacerbation during first baseline year, any AECOPD, even moderate events were associated with an increased risk of death. This risk increases in a graduated manner, meaning with every additional moderate AECOPD there is a further increase in the risk of death. Further, the risk of death associated with severe AECOPD was higher than having any number of moderate AECOPD that we observed. We demonstrated that the risk of mortality associated with severe AECOPD is time dependent with a peak relationship in the first 12 months following severe AECOPD.

With regards to novelty, our study advances knowledge significantly in five areas: 1. Although previous papers (such as Han et al (16)) have shown that year to year - there appears to be variation in AECOPD frequency - our results suggest a more long term stability in rates when observed over up to 10 years of follow-up; 2. Unlike Han et al., we demonstrate that most COPD patients do in fact exacerbate at some point in their history - but a large proportion are likely to become non-exacerbators - suggesting the potential for successfully reducing the AECOPD rate to zero in a sub-group of COPD patients who perhaps respond particularly well to treatment; 3. We are the first to demonstrate a graded effect of AECOPD frequency moving from 0-5+ moderate events per year on long term risk of death; and 4. Uniquely, we were able to compare the risk of death between varying moderate AECOPD frequency and having 1+ severe AECOPD to demonstrate that no number of moderate AECOPD (up to 5+ per year) is equivalent in risk to 1+ severe AECOPD per year. 5. Our case-control analysis indicated that after adjusting for previous AECOPD history, only recent AECOPD frequency is associated with increased risk of death. This finding suggests that the association between historic AECOPD and risk of death may be mitigated by reduction of current AECOPD frequency, i.e. there is no long-term impact of frequent AECOPD if they can be brought under control.

Compared to Han et al.(16), our study is representative of the general COPD population as our study is based on routinely collected electronic health data from patients with a clinical diagnosis of COPD, rather than based on a physiological definition (airflow obstruction among those with a smoking history) among a convenience sample. Compared to Han et al., our study also benefitted from using

observed rather than recalled exacerbation history as the exposure. We expect these differences in the populations might influence exacerbation patterns, and indeed we observed an average of 1.3 AECOPD per year per patient, compared to 0.37 per year per patient in the Han et al. study. This is likely reflected in our finding that around one quarter of COPD patients do not exacerbate over follow up, compared to Han et al.’s finding that around one half did not exacerbate. However compared to Han et al., we did find that a very similar proportion of patients switched from exacerbating to non-exacerbating and vice versa in between the baseline period and first year of follow-up. Although we found that a larger proportion of patients did not exacerbate among those who had a full 10 years of follow up that in the overall study cohort, this sub-cohort will be selectively biased towards survivors who have fewer exacerbations. In patients with COPD, a follow-up longer than 2-3 years is related to relatively high mortality rates due to their advanced mean age, seriousness of their underlying condition and other common morbidities(17).

In our cohort study, increasing frequency of moderate AECOPD was associated with risk of death, although after adjustment for potential confounders this was only significant for those with two or more moderate AECOPD per year. However, having one baseline moderate AECOPD was only associated with an increased risk of death in those patients with incident COPD, perhaps indicating a protective effect of treatment for those with established COPD. The higher relative risk of death associated with severe AECOPD in the one year following COPD diagnosis (incident COPD sub-cohort) likely represents more severe disease in those COPD patients who are hospitalised for their COPD early on in their disease course.

In our case-control study, we found that risk of death increases with increasing frequency of AECOPD, again only for a frequency of 2 or more AECOPD per year, and that the risk of death following severe AECOPD in the last year is 12 times that of those who did not exacerbate at all. In the fully adjusted analysis, the risk of death in the 12 months following severe AECOPD was over 15 times that of those COPD patients who did not have an AECOPD. Our findings suggest that the effect of more distant AECOPD frequency was mediated through higher propensity to have more recent AECOPD, rather than a direct effect of distant AECOPD on risk of death.

The biggest strengths of our study were the representativeness of the cohort, the size, and the 10 years of follow up data. Although there was likely to be a survival bias in the design of the cohort study, this was necessary so that the effect of moderate AECOPD frequency could be compared to the effect of severe AECOPD. In addition, we conducted a case-control study to investigate these effects with a design that did not have a survival bias. Our case-control study also allowed us to investigate the difference in effects of recent versus more distant AECOPD. We also used validated definitions of COPD and AECOPD, which were found to have positive predictive values of over 85% following case note review in previous validation studies (10, 12, 13).

Although we used validated definitions, there is a still the potential for misclassification in electronic healthcare record studies. However, it is likely that any “missed” AECOPD would disproportionately distributed in those who have fairly frequent AECOPD, and this is unlikely to influence our conclusions. We also recognise that other unmeasured confounders for the association between AECOPD frequency and severity, such as frailty, may not have been controlled for. In addition, a further weakness was that we could not assess the natural history and impact of “mild AECOPD” – those events which might be managed at home. One other potential weakness of our study is that some data were missing for covariates, notably FEV1, mMRC score, and BMI. Data were not missing for exposures or outcomes. Further, our results did not change substantially on adjustment for potential confounders, and it is unlikely that missing data on these covariates would change our conclusions.

Conclusions

Our findings highlight the importance of collecting detailed and accurate information on AECOPD frequency and severity in order to consider the risk of future AECOPD and death in terms of therapeutic management. In addition to already published data, we found that the risk of future adverse events in COPD neither starts nor stops with two or more moderate or severe events. Any moderate AECOPD increased susceptibility of future moderate or severe AECOPD and mortality among those with recent incident diagnosis. This increase in risk is stepwise with every additional moderate event leading to more future events. Taken with our finding that a large proportion of our established COPD sub-cohort did not exacerbate, this suggests that reduction in AECOPD frequency to zero is possible, perhaps for a sub-set of patients who respond particularly well to therapy.

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Figure 1. Time to first AECOPD by baseline AECOPD frequency and severity, established COPD patients

Figure 2. Time to first AECOPD by baseline AECOPD frequency and severity, incident COPD patients

Figure 3. Time to death by baseline AECOPD frequency and severity, all patients

Table 1 Baseline study characteristics

Frequency and severity of AECOPD in baseline year

Characteristics Overall 0 moderate 1 moderate 2 moderate 3 moderate 4 moderate 5+ moderate 1+ severe

Patient N 99574 51568 19418 10333 5654 3125 5065 4411

Mean age 66.9 (11.5) 65.8 (11.7) 67.6 (11.2) 67.8 (11.1) 67.7 (11.0) 67.8 (11.1) 67.8 (11.0) 71.0 (10.8)

Sex

Male 53697 (53.9) 28951 (56.1) 10423 (53.7) 5256 (50.9) 2769 (49.0) 1474 (47.2) 2433 (48.0) 2391 (54.2)

Female 45877 (46.1) 22617 (43.9) 8995 (46.3) 5077 (49.1) 2885 (51.0) 1651 (52.8) 2632 (52.0) 2020 (45.8)

Smoking status

Ex-smoker 47650 (47.9) 21443 (41.6) 10357 (53.3) 5504 (53.3) 3159 (55.9) 1760 (56.3) 2983 (58.9) 2444 (55.4)

Current smoker 51924 (52.2) 30125 (58.4) 9061 (46.7) 4829 (46.7) 2495 (44.1) 1365 (43.7) 2082 (41.1) 1967 (44.6)

Mean FEV1 %

predicted, SD (N=48075)

62.1 (21.9) 63.8 (21.7) 62.4 (21.7) 61.1 (21.8) 60.1 (21.9) 59.4 (22.1) 57.0 (22.5) 52.9 (22.3)

Mean MRC score, SD (N=35284)

2.3 (1.0) 2.2 (1.0) 2.3 (1.0) 2.4 (1.0) 2.5 (1.0) 2.6 (1.0) 2.8 (1.1) 2.9 (1.1)

Myocardial infarction

7516 (7.6) 3429 (6.6) 1491 ( 7.7) 873 ( 8.4) 491 ( 8.7) 284 ( 9.1) 427 ( 8.4) 521 (11.8)

Stroke 4533 (4.6) 2152 (4.2) 855 (4.4) 502 (4.9) 255 (4.5) 165 (5.3) 263 (5.2) 341 (7.7)

Heart failure 6827 (6.9) 2847 (5.5) 1329 (6.8) 746 (7.2) 467 (8.3) 273 (8.7) 486 (9.6) 679 (15.4)

Lung cancer 1200 (1.2) 398 (0.8) 248 (1.3) 166 (1.6) 109 (1.9) 63 (2.0) 103 (2.0) 113 (2.6)

Bronchiectasis 2817 (2.8) 914 (1.8) 444 (2.3) 342 (3.3) 254 (4.5) 193 (6.2) 469 (9.3) 201 ( 4.6)

Asthma 32818 (33.0) 14755 (28.6) 6607 (34.0) 3978 (38.5) 2327 (41.2) 1295 (41.4) 2280 (45.0) 1576 (35.7)

GORD 4091 (4.1) 879 (4.5) 488 (4.7) 294 (5.2) 192 (6.1) 314 (6.2) 213 (4.8) 879 (4.5)

Anxiety 5694 (5.7) 1085 (5.6) 667 (6.5) 423 (7.5) 229 (7.3) 472 (9.3) 329 (7.5) 1085 (5.6)

Depression 6265 (6.3) 2943 (5.7) 1164 (6.0) 745 (7.2) 412 (7.3) 254 (8.1) 435 (8.6) 312 (7.1)

Mean BMI, SD (N=92628)

26.9 (6.0) 26.7 (5.8) 26.9 (5.9) 27.1 (6.1) 27.2 (6.4) 27.3 (6.3) 27.0 (6.7) 26.3 (6.5)

Mean IMD decile, SD

5.9 (2.8) 5.9 (2.8) 5.8 (2.8) 6.0 (2.8) 6.0 (2.8) 6.0 (2.8) 6.0 (2.8) 6.1 (2.8)

Inhaled COPD therapy at baseline*

LABA 12669 (16.1) 5295 (14.8) 2484 (15.0) 1599 (17.2) 948 (18.1) 573 (19.4) 968 (20.0) 802 (19.4)

LAMA 26201 (33.2) 9961 (27.8) 5322 (32.1) 3286 (35.3) 2044 (39.1) 1270 (42.9) 2241 (46.3) 2077 (50.2)

ICS 27335 (34.7) 12495 (34.9) 5583 (33.7) 3241 (34.9) 1873 (35.8) 1091 (36.9) 1696 (35.0) 1356 (32.8)

LABA-ICS 36066 (45.7) 13678 (38.2) 7264 (43.8) 4661 (50.1) 2905 (55.5) 1743 (58.9) 3138 (64.8) 2677 (64.7)

LABA-LAMA 41 (0.1) 22 (0.1) 8 (0.0) 6 (0.1) 2 (0.0) 0 (0.0) 0 (0.0) 3 (0.1)

SAMA 14211 (18.0) 5861 (16.4) 2821 (17.0) 1758 (18.9) 1056 (20.2) 632 (21.4) 1067 (22.0) 1016 (24.6)

SABA 64075 (81.2) 28155 (78.6) 13447 (81.1) 7703 (82.8) 4472 (85.5) 2542 (85.9) 4215 (87.0) 3541 (85.6)

No inhaled treatment

20709 (20.8) 15747 (30.5) 2844 (14.6) 1035 (10.0) 421 (7.4) 167 (5.3) 222 (4.4) 273 (6.2)

Abbreviations: BMI, body mass index; FEV1, forced expiratory volume in one second; GORD, gastroesophageal reflux disease; IMD, index of multiple deprivation (socioeconomic status).

* Not mutually exclusive groups

Table 2 – Baseline frequency and severity of AECOPD and risk of moderate AECOPD, severe AECOPD, and death

AECOPD category Adjusted HR (95% CI) time to repeat events future

moderate AECOPD – cohort study

Adjusted HR (95% CI) time to repeat

events future severe AECOPD – cohort

study

Adjusted HR (95% CI) time to death –

cohort study

Adjusted OR (95% CI) risk of death

associated with AECOPD frequency and severity 0-12

months prior – case-control study

Adjusted OR (95% CI) risk of death

associated with AECOPD frequency and severity 12-24

months prior – case-control study

Adjusted OR (95% CI) risk of death

associated with AECOPD frequency and severity 24-36

months prior – case-control study

No AECOPD 1 (reference)

1 (reference)

1 (reference)

1 (reference)

1 (reference)

1 (reference)

1 moderate 1.71 (1.66-1.77)

1.21 (1.14-1.27)

1.01 (0.93-1.11)

1.18 (0.83-1.67)

1.36 (1.02-1.83)

1.38 (1.02-1.87)

2 moderate 2.35 (2.27-2.42)

1.61(1.52-1.72)

1.10 (1.03-1.18)

1.80 (1.19-2.70)

1.56 (1.06-2.31)

1.54 (1.03-2.30)

3 moderate 2.94 (2.83-3.05)

1.89 (1.76-2.03)

1.25 (1.15-1.36)

1.98 (1.13-3.49)

1.50 (0.95-2.37)

1.57 (0.99-2.51)

4 moderate 3.41 (3.27-3.56)

2.14 (1.95-2.35)

1.32 (1.20-1.46)

1.00 (0.53-1.86)

2.23(1.38-3.73)

1.45 (0.75-2.81)

5+ moderate 5.50 (5.32-5.68)

2.92 (2.73-3.13)

1.57 (1.45-1.70)

2.33 (1.45-3.76)

2.50 (1.56-3.98)

2.80 (1.75-4.48)

1+ severe 3.27 (3.13-3.41)

3.69 (3.44-3.94)

1.79(1.65-1.94)

14.16 (9.45-21.20)

4.27(2.78-6.55)

2.57 (1.61-4.13)

All adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Supplementary material

Further details on data source and outcome covariate ascertainment

The CPRD is a very large electronic database of UK general practice data covering 7% of the UK population, and contains information on clinical diagnoses and symptoms (Read codes), test results, referrals to secondary care and some lifestyle factors, such as BMI and smoking status. The Hospital Episodes Statistics (HES), which is linked to CPRD, includes information on dates and diagnoses for hospital admissions. In the UK, 98% of the population are registered with an NHS general practitioner (GP). NHS GPs are the gatekeepers of care to all primary care and planned secondary care services. Patients can only register with one GP at a time. In the CPRD, information is available on date of registration and date of transfer out of the GP practice. Thus we are able to identify periods of patient follow-up in CPRD where we have complete records of all patient care.

We used our previously validated algorithms to identify both moderate(12) and severe AECOPD(13). We defined moderate AECOPD as those managed outside hospital (Read code diagnosis of AECOPD or lower respiratory tract infection, prescription of antibiotics and/ or oral corticosteroids for 5-14 days, or two or more symptoms of AECOPD plus a prescription for either antibiotics or oral corticosteroids). We defined severe AECOPD as those requiring admission to hospital with ICD-10 codes of J44.0, J44.1, or J22 (any position), or J44.9 (first position only). Our AECOPD algorithm has a positive predictive value of over 85%(12). Death was ascertained using linked mortality data.

Read codes were used to identify comorbidities and mMRC dyspnoea score. GOLD grade of airflow limitation was ascertained using Forced Expiratory Volume in one second (FEV1) percent predicted values recorded by GPs and categorized according to GOLD 2017 Grades of airflow limitation(18). BMI values were taken are recorded by GPs. We used the index of multiple deprivation (IMD) at patient level as a measure of socioeconomic status (SES). BMI, mMRC score, and FEV1/GOLD grade were determined using the closest recorded value before the start of follow up (i.e. the latest value before or during the baseline ascertainment year). We recently validated the recording of spirometry values in the CPRD(19). The baseline ascertainment year only was used to identify current asthma, GORD, anxiety and depression. All other comorbidities were ascertained using the whole electronic healthcare record prior to the start of follow-up (i.e. any time during or prior to the baseline ascertainment year).

Cohort study

Entry into the study was dynamic and observation began from COPD diagnosis date, 1 Jan 2004, ‘up-to-standard date’ (date from which data from the GP practice are deemed research quality), or GP practice registration date, whichever was later. Observation ended on 31 March 2015, transfer-out date (date patient left GP practice), or death date, whichever was earlier. The first year of available history was used to categorise patients into exposure groups based on number and severity of AECOPD and was called ‘baseline period’. Outcomes were therefore ascertained during follow-up

period starting from the end of the first complete year of observation; up to a maximum available follow up of ten years and two months. We defined established prevalent COPD as those patients who had their first diagnosis of COPD before the start of the baseline year, and incident disease as those patients who had their first COPD diagnosis on the day of the start of their baseline year. For example, a patient with a diagnosis of COPD in 2000 and who was registered with their CPRD GP practice prior to 2004 would have entered the study at the study start date of 1 Jan 2004 as a patient with established COPD. A patient who registered with their CPRD GP in, for example, 2005, and received a COPD diagnosis in 2007, would have entered the study in 2007 as a patient with incident COPD.

Results of post-hoc analysis on inhaler changing

Among patients who exacerbated in the baseline year, 11.0% of patients received a new ICS containing inhaler in the second six months of this year, 9.5% received a new LABA containing inhaler, and 6.4% received a new LAMA containing inhaler. Use of a new ICS containing inhaler was associated with increased probability of switching from exacerbating in the baseline year to no exacerbations in the first year of follow up (OR 1.11, 1.00-1.22), this effect was evident in those with incident (OR 1.36, 1.16-1.60) but not established disease (OR 0.97, 0.86-1.10). New LAMA containing inhaler prescription was also associated with increased probability of switch from exacerbating to no exacerbations in the first year of follow up (OR 1.14, 1.04-1.24), this was seen in those with established (OR 1.22, 1.09-1.36), but not incident disease (1.03, 0.90-1.19). New LABA prescription was not associated with probability of switching exacerbation status (OR 0.98, 0.88-1.09).

Our interpretation of these findings are that after a failed trial of one therapy, changing to second therapy may help. The reason we believe that switch to LAMA was associated with switch to zero AECOPD in established disease patients and switch to ICS for incident patients is that due to the differences in prescribing patterns over time, established COPD patients were more likely to have had a LABA-ICS as initial treatment at this analysis follow-up start whereas incident patients were more likely to have a LAMA as initial treatment.

Fig S1. Difference between established and incident COPD cohorts. UTS – up to standard date (date at which GP data are regarded as research quality).

Fig S2. Cohort study design

Fig S3. Nested case control study design

Figure S4 – patient flow chart

Patients with a COPD diagnosis in CPRD

N=207,870

Excluded – not eligible for linkage to HES or ONS

N=91,775

Patients with a COPD diagnosis in CPRD and with linked HES and ONS data

N=116,095

Excluded –did not survive first year

N=16,521

Included patients

N=99,574

Figure S5. Time to first AECOPD among all COPD patients by baseline AECOPD frequency and severity

Fig S6 Time to death by baseline AECOPD frequency and severity, incident COPD patients

Fig S7. Time to death by baseline AECOPD frequency and severity, established COPD patients

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Year 1

Incident Established

%

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Year 2

Incident Established

%

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Year 3

Incident Established

%

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Year 4

Incident Established

%

0

1

2

3

4

5

0 10 20 30 40 50 60 70

Year 5

Incident Established

%

Fig S8 – proportion of patients with each frequency of AECOPD in established COPD patients (within 5 years of diagnosis) and incident COPD patients

Table S1. COPD Read codes used in the study

Medcode Read Term18476 COPD follow-up

45771Chronic obstructive pulmonary disease does not disturb sleep

4084 Airways obstructn irreversible794 Emphysema998 Chronic obstructive airways disease1001 Chronic obstructive pulmonary disease5710 Chronic obstructive airways disease NOS9520 Chronic obstructive pulmonary disease monitoring9876 Severe chronic obstructive pulmonary disease10802 Moderate chronic obstructive pulmonary disease10863 Mild chronic obstructive pulmonary disease10980 Centrilobular emphysema11287 Chronic obstructive pulmonary disease annual review14798 Emphysematous bronchitis18621 Chronic obstructive pulmonary disease follow-up18792 Chronic obstructive pulmonary disease monitoring admin23492 Chronic bullous emphysema NOS

26018Chronic obstructive pulmonary disease monitoring by nurse

26306 Chronic bullous emphysema

28755Chronic obstructive pulmonary disease monitoring 1st letter

33450 Emphysema NOS

34202Chronic obstructive pulmonary disease monitoring 2nd letter

34215Chronic obstructive pulmonary disease monitoring 3rd letter

37247 Chronic obstructive pulmonary disease NOS37371 Chronic obstructive pulmonary disease monitoring due44525 Obstructive chronic bronchitis NOS

45998Chronic obstructive pulmonary disease monitoring by doctor

93568 Very severe chronic obstructive pulmonary disease12166 Other specified chronic obstructive airways disease

38074Chronic obstructive pulmonary disease monitor phone invite

42258Chronic obstructive pulmonary disease monitoring verb invite

42313 Health education - chronic obstructive pulmonary disease45770 Chronic obstructive pulmonary disease disturbs sleep

Table S2. Detailed patient characteristics

Frequency and severity of AECOPD in baseline year

Characteristics Overall 0 moderate 1 moderate 2 moderate 3 moderate 4 moderate 5+moderate 1+ severe

Patient N 99574 51568 19418 10333 5654 3125 5065 4411

Age group

<50 8260 (8.3) 5179 (10.0) 1357 (7.0) 652 (6.3) 382 (6.8) 199 (6.4) 314 (6.2) 177 (4.0)

50 to 59 18905 (19.0) 10542 (20.4) 3482 (17.9) 1851 (17.9) 993 (17.6) 560 (17.9) 920 (18.2) 557 (12.6)

60 to 69 31021 (31.2) 16053 (31.1) 6140 (31.6) 3267 (31.6) 1781 (31.5) 1001 (32.0) 1577 (31.1) 1202 (27.3)

70 to 79 28372 (28.5) 13884 (26.9) 5688 (29.3) 3086 (29.9) 1731 (30.6) 916 (29.3) 1561 (30.8) 1506 (34.1)

≥80 13016 (13.1) 5910 (11.5) 2751 (14.2) 1477 (14.3) 767 (13.6) 449 (14.4) 693 (13.7) 969 (22.0)

Sex

Male 53697 (53.9) 28951 (56.1) 10423 (53.7) 5256 (50.9) 2769 (49.0) 1474 (47.2) 2433 (48.0) 2391 (54.2)

Female 45877 (46.1) 22617 (43.9) 8995 (46.3) 5077 (49.1) 2885 (51.0) 1651 (52.8) 2632 (52.0) 2020 (45.8)

Smoking status

Ex-smoker 47650 (47.9) 21443 (41.6) 10357 (53.3) 5504 (53.3) 3159 (55.9) 1760 (56.3) 2983 (58.9) 2444 (55.4)

Current smoker 51924 (52.2) 30125 (58.4) 9061 (46.7) 4829 (46.7) 2495 (44.1) 1365 (43.7) 2082 (41.1) 1967 (44.6)

GOLD grade of airflow limitation

(N=48075)

1 11729 (24.2) 6410 (25.8) 2275 (23.6) 1167 (22.3) 631 (22.3) 353 (22.6) 506 (21.2) 387 (19.7)

2 21403 (44.2) 11389 (45.8) 4367 (45.3) 2306 (44.0) 1164 (41.2) 638 (40.8) 929 (39.0) 610 (31.0)

3 12378 (25.5) 5794 (23.3) 2472 (25.7) 1419 (27.1) 843 (29.9) 454 (29.0) 704 (29.5) 692 (35.1)

4 2965 (6.1) 1269 (5.1) 521 (5.4) 346 (6.6) 186 (6.6) 118 (7.5) 245 (10.3) 280 (14.2)

MRC score (N=35284)

1 7684 (21.8) 4210 (25.6) 1786 (22.5) 790 (19.6) 386 (17.2) 158 (13.1) 227 (12.0) 127 ( 8.4)

2 14466 (41.0) 6970 (42.3) 3414 (43.0) 1659 (41.2) 889 (39.7) 448 (37.2) 615 (32.6) 471 (31.2)

3 8316 (23.6) 3596 (21.8) 1803 (22.7) 990 (24.6) 581 (25.9) 354 (29.4) 546 (29.0) 446 (29.5)

4 4021 (11.4) 1466 (8.9) 806 (10.1) 489 (12.1) 315 (14.1) 202 (16.8) 385 (20.4) 358 (23.7)

5 797 (2.3) 233 (1.4) 135 (1.7) 98 (2.4) 70 (3.1) 42 (3.5) 111 (5.9) 108 (7.2)

Myocardial infarction

7516 (7.6) 3429 (6.6) 1491 ( 7.7) 873 ( 8.4) 491 ( 8.7) 284 ( 9.1) 427 ( 8.4) 521 (11.8)

Stroke 4533 (4.6) 2152 (4.2) 855 (4.4) 502 (4.9) 255 (4.5) 165 (5.3) 263 (5.2) 341 (7.7)

Heart failure 6827 (6.9) 2847 (5.5) 1329 (6.8) 746 (7.2) 467 (8.3) 273 (8.7) 486 (9.6) 679 (15.4)

Lung cancer 1200 (1.2) 398 (0.8) 248 (1.3) 166 (1.6) 109 (1.9) 63 (2.0) 103 (2.0) 113 (2.6)

Bronchiectasis 2817 (2.8) 914 (1.8) 444 (2.3) 342 (3.3) 254 (4.5) 193 (6.2) 469 (9.3) 201 ( 4.6)

Asthma 32818 (33.0) 14755 (28.6) 6607 (34.0) 3978 (38.5) 2327 (41.2) 1295 (41.4) 2280 (45.0) 1576 (35.7)

GORD 4091 (4.1) 879 (4.5) 488 (4.7) 294 (5.2) 192 (6.1) 314 (6.2) 213 (4.8) 879 (4.5)

Anxiety 5694 (5.7) 1085 (5.6) 667 (6.5) 423 (7.5) 229 (7.3) 472 (9.3) 329 (7.5) 1085 (5.6)

Depression 6265 (6.3) 2943 (5.7) 1164 (6.0) 745 (7.2) 412 (7.3) 254 (8.1) 435 (8.6) 312 (7.1)

BMI group (N=92628)

< 19 5600 (6.1) 2724 (5.7) 1063 (5.8) 577 (5.9) 309 (5.8) 182 (6.2) 327 (6.9) 418 (10.3)

19 to 24 32379 (35.0) 17101 (36.0) 6084 (33.3) 3269 (33.5) 1836 (34.4) 933 (31.7) 1679 (35.5) 1477 (36.4)

25 to 29 30848 (33.3) 16003 (33.6) 6297 (34.5) 3226 (33.1) 1698 (31.9) 983 (33.4) 1457 (30.8) 1184 (29.2)

≥30 23801 (25.7) 11739 (24.7) 4809 (26.3) 2673 (27.4) 1487 (27.9) 848 (28.8) 1270 (26.8) 975 (24.1)

IMD decile

1 (least deprived) 6308 (6.7) 3257 (6.8) 1301 (7.1) 649 (6.6) 349 (6.5) 185 (6.2) 299 (6.2) 268 (6.4)

2 7133 (7.6) 3691 (7.7) 1441 (7.8) 731 (7.5) 400 (7.5) 217 (7.3) 357 (7.4) 296 (7.1)

3 9075 (9.7) 4682 (9.7) 1858 (10.1) 957 (9.8) 508 (9.5) 271 (9.1) 460 (9.6) 339 (8.2)

4 9544 (10.2) 4838 (10.0) 1953 (10.6) 1043 (10.6) 521 (9.7) 305 (10.2) 487 (10.1) 397 (9.6)

5 9172 (9.8) 4823 (10.0) 1751 (9.5) 906 (9.2) 508 (9.5) 297 (10.0) 474 (9.9) 413 (9.9)

6 9400 (10.0) 4857 (10.1) 1841 (10.0) 997 (10.2) 522 (9.7) 309 (10.4) 438 (9.1) 436 (10.5)

7 10156 (10.8) 5242 (10.9) 1984 (10.8) 1053 (10.7) 580 (10.8) 314 (10.5) 523 (10.9) 460 (11.1)

8 11382 (12.1) 5921 (12.3) 2185 (11.9) 1144 (11.7) 668 (12.5) 390 (13.1) 582 (12.1) 492 (11.8)

9 10101 (10.8) 5135 (10.6) 1956 (10.6) 1081 (11.0) 577 (10.8) 318 (10.7) 562 (11.7) 472 (11.4)

10 (most deprived) 11450 (12.2) 5777 (12.0) 2123 (11.5) 1242 (12.7) 731 (13.6) 377 (12.6) 617 (12.9) 583 (14.0)

Inhaled COPD therapy at baseline

LABA monotherapy 2602 (4.7) 1195 (5.1) 575 (5.1) 313 (4.7) 163 (4.1) 96 (4.2) 134 (3.4) 126 (4.0)

LAMA monotherapy

6427 (11.7) 3145 (13.3) 1434 (12.6) 684 (10.3) 370 (9.4) 217 (9.5) 293 (7.4) 284 (8.9)

ICS monotherapy 12130 (22.1) 5972 (25.3) 2550 (22.4) 1343 (20.3) 746 (18.9) 422 (18.4) 607 (15.3) 490 (15.4)

LABA ICS dual therapy

21773 (39.6) 9106 (38.6) 4446 (39.1) 2702 (40.9) 1655 (41.9) 949 (41.4) 1669 (42.0) 1246 (39.2)

LABA LAMA dual therapy

697 (1.3) 324 (1.4) 141 (1.2) 62 (0.9) 49 (1.2) 29 (1.3) 47 (1.2) 45 (1.4)

Triple therapy 9950 (18.1) 3289 (13.9) 1918 (16.9) 1334 (20.2) 863 (21.8) 532 (23.2) 1117 (28.1) 897 (28.2)

No inhaled maintenance

treatment

45995 (46.2) 28537 (55.3) 8354 (43.0) 3895 (37.7) 1808 (32.0) 880 (28.2) 1198 (23.7) 1323 (30.0)

Table S3 – Patient characteristics stratified by established and incident disease

Characteristics Established Incident

Age group<50 3628 (7.9) 4632 (8.6)50 to 59 8567 (18.7) 10338 (19.2)60 to 69 13903 (30.4) 17118 (31.8)70 to 79 13465 (29.5) 14907 (27.7)≥80 6136 (13.4) 6880 (12.8)SexMale 24401 (53.4) 29296 (54.4)Female 21298 (46.6) 24579 (45.6)Smoking statusExsmoker 19854 (43.4) 27796 (51.6)Current smoker 25845 (56.6) 26079 (48.4)GOLD grade1 5180 (23.0) 6549 (25.2)2 8988 (39.9) 12415 (47.9)3 6457 (28.7) 5921 (22.8)4 1907 (8.5) 1058 (4.1)MRC score1 949 (14.7) 6735 (23.4)2 2283 (35.3) 12183 (42.3)3 1809 (28.0) 6507 (22.6)4 1163 (18.0) 2858 (9.9)5 262 (4.1) 535 (1.9)Myocardial infarction 3460 (7.6) 4056 (7.5)Stroke 2153 (4.7) 2380 (4.4)Heart failure 3611 (7.9) 3216 (6.0)Lung cancer 430 (0.9) 770 (1.4)Bronchiectasis 1408 (3.1) 1409 (2.6)Asthma 15484 (33.9) 17334 (32.2)GORD 1754 (3.8) 2337 (4.3)Anxiety 2703 (5.9) 2991 (5.6)Depression 3118 (6.8) 3147 (5.8)BMI groupLess than 19 2869 (7.0) 2731 (5.3)19 to 24 15528 (37.9) 16851 (32.6)25 to 29 13405 (32.7) 17443 (33.8)30 and over 9172 (22.4) 14629 (28.3)IMD decile1 2522 (6.1) 3786 (7.2)2 2885 (7.0) 4248 (8.1)3 3728 (9.0) 5347 (10.2)4 4059 (9.8) 5485 (10.5)5 4075 (9.8) 5097 (9.7)6 4228 (10.2) 5172 (9.9)7 4504 (10.9) 5652 (10.8)

8 5271 (12.7) 6111 (11.7)9 4682 (11.3) 5419 (10.4)10 5418 (13.1) 6032 (11.5)Number and severity of baseline AECOPD0 AECOPD 36417 (59.4) 15151 (39.6)1 moderate AECOPD 9947 (16.2) 9471 (24.8)2 moderate AECOPD 5168 (8.4) 5165 (13.5)3 moderate AECOPD 2838 (4.6) 2816 (7.4)4 moderate AECOPD 1626 (2.7) 1499 (3.9)5+ moderate AECOPD 2739 (4.5) 2326 (6.1)1+ severe AECOPD 2608 (4.3) 1803 (4.7)

Table S4. Rate of AECOPD during follow-up stratified by GOLD stage and AECOPD frequency and severity at baseline

Moderate AECOPD Severe AECOPDAECOPD frequency in baseline year

N patients with any event (AECOPD)

% Patients with any event

(AECOPD)

N events Rate per person year (95% CI)

N events Rate per person year (95% CI)

GOLD 1No AECOPD 3420 53.0 17780 0.93

(0.89-0.96)1400 0.08

(0.07-0.08)1 moderate 2048 87.3 14899 1.40

(1.34-1.46)922 0.09

(0.08-0.10)2 moderate 1085 91.8 10841 1.98

(0.88-2.08)628 0.12

(0.10-0.14)3 moderate 598 93.2 7381 2.55

(2.40-2.72)530 0.19

(0.15-0.23)4 moderate 340 95.0 5215 3.29

(3.04-3.56)303 0.20

(0.16-0.26)5+ moderate 487 97.8 11071 4.81

(4.54-5.10)546 0.25

(0.20-0.30)1+ severe 369 94.1 4483 2.96

(2.71-3.24)770 0.53

(0.44-0.63)GOLD 2No AECOPD 7033 59.9 38233 0.98

(0.95-1.01)2508 0.07

(0.06-0.07)1 moderate 4115 89.4 32947 1.50

(1.45-1.54)1853 0.09

(0.08-0.09)2 moderate 2215 93.0 23060 2.01

(1.94-2.09)1239 0.11

(0.1-0.12)3 moderate 1113 94.6 14624 2.55

(2.44-2.67)756 0.14

(0.12-0.16)4 moderate 630 96.6 9863 3.22 452 0.15

(3.04-3.40) (0.13-0.18)5+ moderate 922 97.5 21340 4.76

(4.57-4.96)925 0.21

(0.19-0.24)1+ severe 582 92.2 7266 2.80

(2.58-3.04)785 0.31

(0.27-0.35)GOLD 3No AECOPD 3847 62.8 25126 1.24

(1.20-1.29)2784 0.14

(0.13-0.15)1 moderate 2411 92.3 22105 1.73

(1.67-1.80)2143 0.17

(0.16-0.19)2 moderate 1402 95.2 17497 2.40

(2.30-2.51)1564 0.22

(0.2-0.25)3 moderate 844 97.2 13299 3.06

(2.91-3.22)1130 0.27

(0.23-0.3)4 moderate 455 97.4 8321 3.60

(3.38-3.84)609 0.28

(0.24-0.32)5+ moderate 697 98.7 17255 5.04

(4.83-5.27)1295 0.39

(0.35-0.45)1+ severe 672 94.0 8563 3.01

(2.80-3.23)1565 0.57

(0.51-0.63)GOLD 4No AECOPD 823 61.8 5613 1.40

(1.30-1.51)869 0.22

(0.2-0.25)1 moderate 508 91.7 4790 1.90

(1.76-2.06)675 0.27

(0.23-0.33)2 moderate 354 97.3 4514 2.55

(2.38-2.73)548 0.31

(0.27-0.36)3 moderate 184 94.4 3126 3.65

(3.32-4.03)333 0.42

(0.34-0.51)4 moderate 118 98.3 2238 3.68

(3.32-4.10)256 0.46

(0.33-0.66)5+ moderate 245 99.2 6311 5.61 557 0.52

(5.22-6.04) (0.44-0.62)1+ severe 270 95.1 3807 3.44

(3.1-3.82)713 0.65

(0.56-0.76)

Table S5- Baseline severity and frequency of AECOPD and risk of moderate AECOPD by established and incident COPD, Cox proportional hazard models

Baseline AECOPD category

N events Rate per year (95% CI) – age adjusted

Crude HR (95% CI) time to first

Adjusted HR (95% CI) time to first*

Adjusted HR (95% CI) time to first-

established COPD group*

Adjusted HR (95% CI) time to first- incident COPD

group*

No AECOPD 23615 0.42 (0.42-0.43)

1 (reference)

1 (reference)

1 (reference)

1 (reference)

1 moderate 15490 0.77 (0.76-0.78)

1.49 (1.46-1.53)

1.40 (1.35-1.46)

1.41 (1.27-1.56)

1.40 (1.34-1.46)

2 moderate 8949 1.20 (1.17-1.22)

2.09 (2.04-2.14)

1.81 (1.72-1.90)

1.91 (1.70-2.15)

1.79 (1.69-1.89)

3 moderate 5104 1.73 (1.68-1.78)

2.89 (2.80-2.98)

2.40 (2.26-2.55)

2.35 (2.05-2.68)

2.39 (2.23-2.56)

4 moderate 2921 2.52 (2.43-2.61)

3.95 (3.80-4.11)

3.22 (2.99-3.49)

3.10 (2.60-3.69)

3.24 (2.97-3.54)

5+ moderate 4887 4.51 (4.38-4.68)

6.75 (6.54-6.96)

5.72 (5.37-6.11)

6.02 (5.26-6.90)

5.54 (5.14-5.97)

1+ severe 3566 1.38 (1.34-1.43)

2.55 (2.46-2.64)

2.12 (1.97-2.29)

2.17 (1.86-2.53)

2.09 (1.92-2.29)

* Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Table S6 – Baseline severity and frequency of AECOPD and risk of moderate AECOPD by established and incident COPD, Andersen-Gill models

Baseline AECOPD category

N events Rate per year (95% CI) Adjusted HR (95% CI) time to repeat events- established COPD

group*

Adjusted HR (95% CI) time to repeat events - incident COPD

group*

No AECOPD 143696 0.99 (0.98-1.01)

1 (reference)

1 (reference)

1 moderate 124917 1.52 (0.49-0.54)

1.41 (1.39-1.43)

1.46 (1.44-1.49)

2 moderate 93091 2.11 (2.08-2.15)

1.90 (1.87-1.93)

1.97 (1.94-2.01)

3 moderate 63031 2.69 (2.64-2.75)

2.39 (2.35-2.44)

2.55 (2.51-2.60)

4 moderate 43451 3.35 (3.27-3.44)

2.77 (2.71-2.82)

3.12 (3.04-3.19)

5+ moderate 98943 4.98 (4.89-5.07)

4.07 (4.01-4.13)

4.40 (4.32-4.48)

1+ severe 42896 3.00 (2.91-3.10)

2.56(2.50-2.61)

2.49 (2.43-2.56)

* Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Table S7- Baseline severity and frequency of AECOPD and risk of severe AECOPD, Cox proportional hazard models

Baseline AECOPD category

N events Rate per year (95% CI) Crude HR (95% CI) time to first

Adjusted HR (95% CI) time to first*

Adjusted HR (95% CI) time to first- prevalent

COPD*

Adjusted HR (95% CI) time to first- incident COPD*

No AECOPD 8896 0.07 (0.06-0.07)

1 (reference)

1 (reference)

1 (reference)

1 (reference)

1 moderate 5994 0.08 (0.08-0.08)

1.07 (1.04-1.11)

1.05 (0.97-1.14)

1.07 (1.02-1.13)

1.06 (1.01-1.13)

2 moderate 3772 0.10 (0.10-0.10)

1.16 (1.11-1.20)

1.10 (1.01-1.21)

1.19 (1.12-1.25)

1.13 (1.05-1.21)

3 moderate 2253 0.11 (0.11-0.12)

1.24 (1.18-1.30)

1.16 (1.01-1.30)

1.30 (1.21-1.39)

1.17 (1.07-1.27)

4 moderate 1446 0.14 (0.13-0.15)

1.38 (1.30-1.45)

1.31 (1.15-1.50)

1.44 (1.33-1.55)

1.35 (1.21-1.50)

5+ moderate 2583 0.17 (0.16-0.18)

1.61 (1.54-1.68)

1.47 (1.32-1.64)

1.72 (1.62-1.83)

1.46 (1.34-1.59)

1+ severe 2675 0.28 (0.27-0.29)

1.95 (1.87-2.03)

1.69 (1.52-1.88)

2.13 (2.00-2.26)

1.64 (1.51-1.78)

* Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Table S8- Baseline severity and frequency of AECOPD and risk of severe AECOPD by established and incident COPD, Andersen-Gill models

Baseline AECOPD category N events Rate per patient year (95% CI) Adjusted HR (95% CI) time to repeat events- established COPD

group*

Adjusted HR (95% CI) time to repeat events - incident COPD

group*

No AECOPD 13730 0.10 (0.09-0.10)

1 (reference)

1 (reference)

1 moderate 10209 0.12 (0.12-0.13)

1.18 (1.13-1.23)

1.23 (1.18-1.29)

2 moderate 7387 0.17 (0.16-0.18)

1.61 (1.55-1.68)

1.54 (1.47-1.62)

3 moderate 4817 0.21 (0.19-0.22)

1.88 (1.79-1.97)

1.79 (1.68-1.91)

4 moderate 3197 0.25 (0.23-0.27)

2.04 (1.93-2.16)

2.16 (2.01-2.33)

5+ moderate 6640 0.33 (0.32-0.35)

2.81 (2.69-2.93)

2.80 (2.65-2.98)

1+ severe 7313 0.51 (0.49-0.54)

3.57 (3.42-3.72)

3.61 (3.42-3.82)

* Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Baseline AECOPD category

N events Rate per 1000 patient years (95% CI)

Adjusted HR (95% CI) established COPD group*

Adjusted HR (95% CI) incident COPD group*

No AECOPD 10896 38.4 (37.7-39.1)

1 (reference)

1 (reference)

1 moderate 3810 48.9 (47.4-50.5)

0.95 (0.87-1.03)

1.07 (1.00-1.15)

2 moderate 1783 54.5 (52.4-56.8)

1.06 (0.96-1.17)

1.12 (1.03-1.24)

3 moderate 920 61.5 (58.3-64.8)

1.25 (1.11-1.40)

1.21 (1.07-1.36)

4 moderate 489 68.6 (64.2-73.4)

1.27 (1.11-1.46)

1.33 (1.15-1.55)

5+ moderate 813 83.4 (79.4-87.6)

1.52 (1.37-1.69)

1.51 (1.33-1.71)

1+ severe 2407 120.5 (114.8-126.5)

1.64 (1.46-1.83)

1.92 (1.71-2.15)

Table S9- baseline AECOPD and risk of death stratified by incident and established COPD groups

* Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted

Table S10. Odds of mortality by prior severity and frequency of AECOPD, Case-Control analysis

N of cases (%)

N of controls (%) Minimally adjusted OR (95% CI)*

Maximally adjusted OR (95% CI)**

Maximally adjusted covariates and AECOPD frequency at other

time points OR (95% CI)***Number and severity of AECOPD 0-12 months priorNo AECOPD 3698 (52.5) 15051 (72.4) 1

(reference)1

(reference)1

(reference)1 moderate 438 (6.2) 1951 (9.4) 1.29

(1.14-1.45)1.18

(0.83-1.67)1.29

(0.88-1.87)2 moderate 278 (4.0) 1123(5.4) 1.46

(1.26-1.70)1.80

(1.19-2.70)2.07

(1.32-3.23)3 moderate 215 (3.1) 638 (3.1) 1.97

(1.66-2.33)1.98

(1.13-3.49)2.39

(1.29-4.43)4 moderate 147(2.1) 405 (2.0) 2.14

(1.74-2.63)1.00

(0.53-1.86)1.03

(0.52-2.03)5+ moderate 365 (5.2) 781 (3.7) 2.82

(2.43-3.25)2.33

(1.45-3.76)2.64

(1.50-4.66)1+ severe 1903 (27.0) 844 (4.1) 12.96

(11.62-14.46)14.16

(9.45-21.2)15.86

(9.98-25.22)Number and severity of AECOPD 12-24 months priorNo AECOPD 4385 (62.3) 15346 (73.8) 1

(reference)1

(reference)1

(reference)1 moderate 611 (8.7) 1913 (9.2) 1.30

(1.17-1.44)1.36

(1.02-1.83)1.09

(0.86-1.37)2 moderate 345 (4.9) 1152 (5.5) 1.20

(1.06-1.37)1.56

(1.06-2.31)0.99

(0.74-1.32)3 moderate 281 (4.0) 653 (3.1) 1.75

(1.50-2.03)1.50

(0.95-2.37)0.92

(0.64-1.30)4 moderate 212 (3.0) 393 (1.9) 2.19 2.23 1.19

(1.84-2.61) (1.38-3.73) (0.80-1.77)5+ moderate 505 (7.2) 761 (3.7) 2.7

(2.38-3.06)2.50

(1.56-3.98)0.99

(0.69-1.42)1+ severe 705 (10.0) 575 (2.8) 5.02

(4.44-5.69)4.27

(2.78-6.55)1.42

(1.03-1.95)Number and severity of AECOPD 24-36 months priorNo AECOPD 4733 (67.2) 16062 (77.3) 1

(reference)1

(reference)1

(reference)1 moderate 610 (8.7) 1786 (8.6) 1.29

(1.16-1.43)1.38

(1.02-1.87)0.87

(0.69-1.11)2 moderate 389 (5.5) 972 (4.7) 1.53

(1.34-1.73)1.54

(1.03-2.30)0.93

(0.69-1.243 moderate 257 (3.7) 594 (2.9) 1.67

(1.43-1.96)1.57

(0.99-2.51)0.85

(0.60-1.22)4 moderate 150 (2.1) 322 (1.6) 1.74

(1.42-2.13)1.45

(0.75-2.81)0.71

(0.44-1.13)5+ moderate 417 (5.9) 622 (3.0 2.51

(2.20-2.87)2.80

(1.75-4.48)0.88

(0.61-1.25)1+ severe 488 (6.9) 435 (2.1) 4.22

(3.67-4.85)2.57

(1.61-4.13)1.07

(0.76-1.51)

* Age, sex, and smoking status adjusted.

** Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted.

*** Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted, and other time points.

Table S11 Odds of severe AECOPD by prior severity and frequency of AECOPD, Case-Control analysis

N of cases (%) N of controls (%) Minimally adjusted OR (95% CI)*

Maximally adjusted OR (95% CI)**

Maximally adjusted OR (95% CI) including adjustment for other time

periods***Number and severity of AECOPD 0-12 months priorNo AECOPD 3938 (50.0) 18358 (77.6) 1

(reference)1

(reference)1

(reference)1 moderate 678 (8.6) 256 (1.1) 31.86

(26.24-38.70)24.19

(17.85-32.79)10.56

(7.50-14.87)2 moderate 599 (7.6) 177 (0.8) 38.20

(30.66-47.60)29.99

(21.05-42.73)12.43

(8.36-18.50)3 moderate 431 (5.5) 147 (0.6) 36.93

(29.03-46.98)27.56

(19.00-36.99)9.38

(6.21-14.15)4 moderate 290 (3.7) 102 (0.4) 30.88

(23.44-40.69)23.42

(15.31-35.83)8.07

(5.04-12.91)5+ moderate 793 (10.0) 64 (1.1) 32.95

(27.23-39.88)21.68

(16.03-29.31)8.35

(5.68-12.26)1+ severe 1155 (14.7) 4348 (18.4) 2.81

(2.53-3.13)2.17

(1.84-2.56)2.44

(1.96-3.05)Number and severity of AECOPD 12-24 months priorNo AECOPD 4307 (54.6) 18630 (78.8) 1

(reference)1

(reference)1

(reference)1 moderate 820 (10.4) 290 (1.2) 21.88

(18.41-26.02)18.1

(13.66-23.98)6.72

(4.90-9.20)2 moderate 561 (7.1) 191 (0.8) 24.2

(19.72-29.74)18.70

(13.42-26.03)4.95

(3.36-7.29)3 moderate 423 (5.4) 140 (0.6) 26.75

(21.06-33.98)21.67

(14.87-31.58)5.71

(3.66-8.90)4 moderate 298 (3.8) 113 (0.5) 20.99

(16.08-27.41)14.99

(9.76-23.03)2.99

(1.80-4.97)5+ moderate 619 (7.9) 245 (1.0) 20.41 13.68 3.23

(16.84-24.74) (10.06-18.59) (2.12-4.91)1+ severe 856 (10.9) 4043 (17.1) 1.65

(1.48-1.83)1.23

(1.04-1.45)1.07

(0.85-1.36)Number and severity of AECOPD 24-36 months priorNo AECOPD 5068 (64.3) 19050 (80.5) 1

(reference)1

(reference)1

(reference)1 moderate 758 (9.6) 313 (1.3) 13.07

(11.11-15.38)8.56

(6.68-10.98)2.15

(1.58-2.93)2 moderate 464 (5.9) 217 (0.9) 11.91

(9.81-14.45)12.25

(8.83-16.98)2.57

(1.72-3.84)3 moderate 350 (4.4) 141 (0.6) 12.34

(9.81-15.52)8.63

(6.13-12.17)1.51

(0.98-2.31)4 moderate 206 (2.6) 89 (0.4) 13.23

(9.90-17.67)12.16

(7.40-19.96)1.82

(1.00-2.52)5+ moderate 487 (6.2) 205 (0.9) 12.61

(10.35-15.35)9.18

(6.68-12.60)1.64

(1.07-2.52)1+ severe 551 (7.0) 3637 (15.4) 0.79

(0.71-0.89)0.71

(0.60-0.84)0.54

(0.42-0.69)* Age, sex, and smoking status adjusted.

** Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted.

*** Adjusted for age, sex, smoking status, BMI, co-morbidities, FEV1 % predicted, and other time points.

We identified 7884 cases (severe AECOPD) and each of these were matched on age and GP practice to three controls. We found that those who exacerbated at all were at higher risk of severe AECOPD after adjustment for confounders. Having a severe AECOPD between 2-3 years previously (and then surviving) was associated with decreased risk of severe AECOPD.

The findings from the case-control study investigating severe AECOPD as an outcome indicate that those who exacerbate (moderate AECOPD 1-5+) seem to be at the same level of higher risk of severe AECOPD. Recent severe AECOPD was associated with a lower risk of further AECOPD than moderate AECOPD at all time points, and was even protective for those with severe AECOPD 24-36 months previously. Given our findings on the high risk of death following

severe AECOPD, this likely represents the effects of competing risk of death for further severe AECOPD, and in the case of the protective effect of severe AECOPD in the previous 24-36 months, a healthy survivor effect. In addition, the decreasing risk of severe AECOPD associated with increasing moderate AECOPD frequency in the last 0-12 months after adjustment for frequency at other time points possibly represents the impact of increased treatment and hospital avoidance strategies for patients who are having very frequent AECOPD.

Table S11. Switch in AECOPD frequency between baseline and 1st year of follow up – all AECOPD (moderate and severe)

All

Number of AECOPD in 1st year follow up Switch zero to any (%)

Switch any to zero by frequency

(%)

Switch FE to IE by

frequency (%)

Switch IE to FE by

frequency (%)

Baseline AECOPD number

0 1 2 3 4 5+Row Tota

l% % % % % % %

0 72.6 16.7 6.5 2.5 1.0 0.8 100 27.4 10.8

1 40.3 29.1 15.8 7.7 3.8 3.3 100 40.3 30.6

2 27.4 26.7 19.4 11.9 6.8 7.9 100 27.4 54.1

3 18.5 21.2 21.2 15.1 10.2 13.9 100 18.5 39.7

4 11.3 17.3 18.0 16.0 12.6 24.7 100 11.3 28.6

5+ 5.6 9.4 10.1 11.9 11.0 52.1 100 5.6 15.0

Established COPD Number of AECOPD in 1st year follow up

Baseline AECOPD number

0 1 2 3 4 5Row Tota

l% % % % % % %

0 84.5 9.2 3.8 1.4 0.7 0.5 100 15.5 6.4

1 50.4 23.2 13.0 6.8 3.5 3.1 100 50.4 26.4

2 34.3 21.9 17.6 11.2 6.7 8.1 100 34.3 56.2

3 24.3 18.3 19.4 13.5 10.0 14.5 100 24.3 42.6

4 14.9 15.0 15.9 15.0 13.1 26.1 100 14.9 29.9

5+ 7.6 8.1 9.3 11.3 9.9 53.9 100 7.6 15.7

Incident COPD

Number of AECOPD in 1st year follow upBaseline AECOPD number

0 1 2 3 4 5Row Tota

l% % % % % % %

0 46.7 32.9 12.4 5.0 1.7 1.4 100 53.3 20.5

1 30.6 34.7 18.5 8.6 4.1 3.6 100 30.6 34.8

2 20.8 31.1 21.0 12.6 6.9 7.6 100 20.8 51.9

3 12.9 24.0 22.9 16.6 10.3 13.3 100 12.9 36.9

4 7.5 19.9 20.3 17.1 12.0 23.3 100 7.5 27.4

5+ 3.2 10.9 10.9 12.6 12.4 50.0 100 3.2 14.1