# Risk of cardiovascular events according to the severity of an exacerbation of chronic obstructive pulmonary disease

Maeva Zysman, Clementine Nordon, Caroline Fabry-Vendrand, Kirsty Rhodes, Oriane Bretin, Amayelle Rey, Cedric Collin, Nolwenn Poccardi, Victor Aboyans

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Maeva Zysman, Clementine Nordon, Caroline Fabry-Vendrand, Kirsty Rhodes, Oriane Bretin, et al. Risk of cardiovascular events according to the severity of an exacerbation of chronic obstructive pulmonary disease. European Journal of Preventive Cardiology, 2025, 10.1093/eurjpc/zwaf086. hal-05122347

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# Risk of cardiovascular events according to the severity of an exacerbation of chronic obstructive pulmonary disease

Maeva Zysman ID<fnref n="1" />*, Clementine Nordon², Caroline Fabry-Vendrand³, Kirsty Rhodes², Oriane Bretin⁴, Amayelle Rey⁴, Cedric Collin⁴, Nolwenn Poccardi³, and Victor Aboyans ID⁵

Received 27 November 2024; revised 24 January 2025; accepted 13 February 2025; online publish-ahead-of-print 20 February 2025

**Aims**

Risk estimation of different types of cardiovascular events (CVEs) following a hospitalization for exacerbated chronic obstructive pulmonary disease (exCOPD) is warranted to consider prevention.

**Methods and results**

A case-crossover study was conducted using the French exhaustive hospital discharge database (2013–19). Case-patients had a diagnosis of chronic obstructive pulmonary disease, were hospitalized for a CVE in France in 2018–19 (admission date was index date) with no other CVE in ≤12 months, and had ≥1 hospitalization for exCOPD ≤24 weeks before index CVE. The key exposure was hospitalization for exCOPD (overall and according to levels of care intensity) ≤1–4 weeks vs. 9–24 weeks preceding the CVE. Conditional logistic regression models estimated odds ratios (ORs) for the association between hospitalization for exCOPD and different types of CVE. Among 9840 case-patients, the most frequent CVE was decompensated heart failure (5888 case-patients, 59.8%). The CVE risk was greater ≤4 weeks after a hospitalization for any exCOPD [OR, 3.03; 95% confidence interval (CI), 2.90–3.16] and seven times greater if mechanical ventilation was necessary (OR, 6.99; 95% CI, 6.09–8.03). The risk of non-ST-elevation myocardial infarction (OR, 5.33; 95% CI, 4.47–6.34) was the highest among CVE. The risk was also significantly increased (P <0.05) for many other CVEs: ST-elevation myocardial infarction (OR, 4.24), resuscitated cardiac arrest (OR, 4.33), pulmonary embolism (OR, 4.02), atrial fibrillation/ flutter (OR, 3.03), ischaemic stroke (OR, 1.93), and limb events (OR, 1.34). Ten percent of CVEs were fatal.

**Conclusion**

Following hospitalization for exCOPD, the risk of cardiovascular complications is increased. These patients require close and sustained monitoring to mitigate CVE risk.

**Lay summary**

This study used records from the French hospital discharge database, to determine whether the risk of a severe cardiovascular event increased after patients were hospitalized for an exacerbation of chronic obstructive pulmonary disease.

<footnote n="1">¹Service des maladies respiratoires, U1045, CIC 1401, Univ-Bordeaux, CHU de Bordeaux, Hôpital Xavier Arnozan, Avenue du Haut Lévèque, 33600 Pessac, France; ²Global Evidence Strategy—Respiratory, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK; ³Medical, AstraZeneca France, Courbevoie, France; ⁴Real World Solution, IQVIA Opérations, Courbevoie, France; and ⁵Department of Cardiology, Dupuytren University Hospital, and EpiMaCT, Inserm1094/IRD270, Limoges University, Limoges, France</footnote>

<footnote>* Corresponding author. Tel: 05 47 30 27 50, Email: maeva.zysman@chu-bordeaux.fr, Twitter: MaevaZysman</footnote>

<footnote>**Prior abstract publication/presentation:** Data from this manuscript have been presented at European Respiratory Society (ERS) 2024 and European Society of Cardiology (ESC) 2024.</footnote>

<footnote>© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.</footnote>

<footnote>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.</footnote>
## Graphical Abstract

<figure><img src="image_2.png" /></figure>

EXACOS-CV
France

**Objective:** To quantify the risk of a CV event following a COPD exacerbation overall and by subtype of CV event

<figure><img src="image_3.png" /></figure>

## Keywords

Cardiovascular events • Case-crossover study • Chronic obstructive pulmonary disorder

## Introduction

Chronic obstructive pulmonary disease is a chronic disorder characterized by airflow obstruction and an increased inflammatory response of the lungs. It is the third leading cause of death worldwide.¹ In France, more than 2.6 million individuals live with chronic obstructive pulmonary disease (3.2–7.5% of individuals ≥40 years old).² This condition is strongly associated with cardiovascular diseases³ through shared biological, social, and environmental risk factors (e.g. ageing, obesity, smoking, or exposure to air pollution),⁴ and disease interactions worsen the morbidity and mortality of disease.⁵ Exacerbations of chronic obstructive pulmonary disease are periods of acute worsening of dyspnoea, cough, or sputum volume that require a change in treatment that can be managed in the outpatient setting (moderate) or that require a hospitalization (severe).⁶ Exacerbations can irreversibly reduce lung function,⁷ accelerate the rate of subsequent exacerbations, and lead to premature death from respiratory and cardiovascular causes.⁸

Recent studies have shown that the risk of a hospitalization for a cardiovascular event (CVE) or death⁹ was markedly increased following either a moderate or a severe chronic obstructive pulmonary disease exacerbation, and risk was highest after a severe exacerbation.¹⁰⁻¹³ However, chronic obstructive pulmonary disease exacerbations that require a hospitalization can be managed in various ways depending on the intensity of respiratory symptoms or presence of systemic inflammation. To our knowledge, no previous studies explored the impact of chronic obstructive pulmonary disease exacerbations on the risk of CVEs according to the level of exacerbation severity and intensity of inpatient management. Previous studies have established that the risk increases with a variety of different types of CVEs such as decompensated heart failure, acute coronary syndrome, arrhythmias, pulmonary embolism, pulmonary artery hypertension, and ischaemic stroke; however, none have explored

the categories of these CVEs with more granularity in the same population. Understanding which types of CVEs occur the most after hospitalization for a chronic obstructive pulmonary disease exacerbation, and the period at increased risk for it, may provide hints for preventive measures to avoid or decrease subsequent cardiovascular events.

We aimed to quantify the association between hospitalization for chronic obstructive pulmonary disease exacerbation and acute cardiac, cerebrovascular, or peripheral (collectively called cardiovascular) events: (i) overall and in specific types of acute CVEs; (ii) in relation to the severity of exacerbations and intensity of inpatient management; and (iii) in various subgroups of patients to identify patients most at risk.

## Methods

This study used a case-crossover design to explore the effect of transient exposures on the risk of acute events.¹⁴ The case-crossover design is a case-only design that uses each case as its own control and can thus effectively control for observed and unobserved time invariant confounders (e.g. demographic and behavioural risk factors). We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.¹⁵

## Data source

Data from 1 January 2013 to 31 December 2019 (study period) were extracted from the French hospital discharge database (Programme de Medicalisation des Systèmes d'Information, PMSI),¹⁶ an exhaustive national medico-administrative database that includes all inpatients admitted to any public or private hospital in France. All inpatient stays are recorded at an individual level with patients' age and sex, admission date, length of stay, type of ward, primary diagnosis code (i.e. reason for admission), other relevant comorbid disease codes (secondary codes), and medical procedures performed during the hospitalization. Medical codes use the
International Classification of Diseases, Tenth Edition (ICD-10), and procedure codes use the French Common Classification of Medical Procedures.¹⁷

## Study population and ethics

The source population consisted of individuals with chronic obstructive pulmonary disease identified as those with any hospitalization with a primary or secondary code for chronic obstructive pulmonary disease (ICD-10 codes are listed in Supplementary material online, Table S1) during the study period and age ≥40 years upon the earliest qualifying hospitalization. Within the source population, case-patients were those hospitalized for a CVE of interest between 1 January 2018 and 31 December 2019. These included myocardial infarction [overall, and ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI) separately], unstable angina, decompensated heart failure, atrial fibrillation or flutter, resuscitated cardiac arrest, pulmonary embolism, major limb events, and ischaemic stroke (ICD-10 codes are listed in Supplementary material online, Table S2).¹⁸ The admission date was the index date. Individuals hospitalized for another CVE the year prior to the index date were excluded to avoid counting recurring cardiovascular events.

This study was conducted in accordance with the Declaration of Helsinki and was conducted according to the current legislation and national recommendations. Patient consent was not required. The use of PMSI data was authorized by the French National Commission for Data Protection (Commission Nationale de l'Informatique et des Libertés) through MR-006 methodology¹⁹ and captured through the technical French Agency for Information on Hospital Care (ATIH).

## Exposure

The exposure of interest was a hospitalization for a chronic obstructive pulmonary disease exacerbation identified using a validated algorithm (see Supplementary material online, Figure S1).²,²⁰ Exacerbations were categorized as either severe (admission in general ward), very severe (severe with acute respiratory failure), critical [admission to the intensive care unit (ICU)], or life-threatening (critical with mechanical ventilation; Supplementary material online, Table S3).⁹ Exposure to a chronic obstructive pulmonary disease exacerbation was measured within the 24 weeks preceding the index date. In line with Reilev et al.,²¹ the at-risk (case) time window—during which the risk of a CVE following a chronic obstructive pulmonary disease exacerbation is deemed maximum—was the 4-week period just preceding the index date. The control time windows (reference periods) were the 9–24 weeks preceding the index date, split into four control time windows of 4 weeks each (Figure 1). Four control time windows were used to increase statistical precision. A wash-out time window (5–8 weeks preceding the index date) was used to minimize the risk of a carryover effect of exacerbations. The date of admission for a chronic obstructive pulmonary disease exacerbation was used to assign an exposure status to each time window.

## Statistical analysis

Analyses were conducted with SAS Version 9.4 (SAS Institute, Cary, US) software. Missing data were described when identifiable and not imputed.

The case-crossover analysis population was the subset of case-patients who were hospitalized at least once for a chronic obstructive pulmonary disease exacerbation within the 24 weeks preceding the index date (Figure 2). To describe how the population characteristics changed from the source population to the case-patient population and, in turn, to the case-crossover analysis population, characteristics of the three populations were summarized. As the case-crossover study design provided a within-person comparison between exposure status in the at-risk time window and exposure status in the control time windows, case-patients who are always exposed or never exposed in all at-risk and control time window(s) ('concordant patients') did not contribute to the analysis.

Subsequent analyses were conducted in the case-crossover analysis population. The median [interquartile range (IQR)] number of days elapsed between the latest hospitalization for a chronic obstructive pulmonary

disease exacerbation and the subsequent CVE was described overall and by type of CVE. This was also done for exacerbations categorized by level of severity. Odds of exposure during the at-risk period were compared to odds of exposure in control windows using conditional logistic regression models that provided odds ratios (ORs) and corresponding 95% confidence intervals (95% Cls). First, we estimated the association between a hospitalization for chronic obstructive pulmonary disease exacerbation and (i) a CVE of any type (composite outcome), (ii) each type of CVE separately, and (iii) in-hospital death following a CVE. Then, we estimated the association between a hospitalization for chronic obstructive pulmonary disease exacerbation categorized by severity level and a CVE (composite outcome). Finally, we estimated the association between a hospitalization for chronic obstructive pulmonary disease exacerbation and a CVE (composite outcome) in various subgroups of case-patients stratified by: (i) age—categorized into <65, 65–74, 75–79, and ≥80 years old; (ii) male or female sex; (iii) quintile of social deprivation index;²² and (iv) season of the CVE (spring from March to May, summer from June to August, autumn from September to November, and winter from December to February). Models were not adjusted.²³ No adjustment was made for multiple comparisons because of the high correlation between the different outcomes explored.

Two sensitivity analyses were conducted to assess the impact of time window duration on association. The first analysis used time windows of 2 weeks (and thus focused on patients hospitalized for an exacerbation in the 12 weeks preceding the CVE). The second analysis used time windows of 8 weeks (and thus focused on patients hospitalized for an exacerbation in the 48 weeks preceding the CVE).

## Results

The source population consisted of 1 253 391 individuals with chronic obstructive pulmonary disease identified during the study period in France, including 122 172 (9.7%) case-patients who had a CVE in 2018–19 (Figure 2). Patient characteristics are presented in Supplementary material online, Tables S4 and S5. Among case-patients, 9840 were also hospitalized at least once for a chronic obstructive pulmonary disease exacerbation within the 24 weeks preceding their CVE and formed the case-crossover analysis population. Their mean age was 76.8 years [standard deviation (SD), 10.7] and 6496 (66.0%) were male (Table 1). The most frequent CVE was decompensated heart failure (n = 5888, 59.8%) followed by acute coronary syndrome (n = 1070, 10.9%). In 950 (9.7%) individuals, the CVE was followed by in-hospital death. A total of 12 134 hospitalizations for chronic obstructive pulmonary disease exacerbation occurred within the 24 weeks preceding the CVE as 17.4% of people had ≥2 hospitalizations. Among these exacerbations, 6202 (51.1%) were severe, 2561 (21.1%) were very severe, 2308 (19.0%) were critical, and 1063 (8.8%) were life-threatening exacerbations.

## Temporality between exacerbation and cardiovascular event

The daily number of chronic obstructive pulmonary disease exacerbations was notably higher in the 4 weeks preceding the CVE than in any of the control time windows (see Supplementary material online, Figure S2). The overall median time to the CVE was 43 days, and 25% of events occurred within the first 2 weeks (IQR, 14–92; Supplementary material online, Figure S3). The smallest median time to the event was observed for NSTEMI (23.5 days; IQR, 5.5–78) and resuscitated cardiac arrest (28 days; IQR, 9–83), whereas the greatest median time to event was observed for ischaemic stroke (62 days; IQR, 22–111) and major limb events (67.5 days; IQR, 31–119). Concerning exacerbation severity, the median time to the CVE was shorter following exacerbations managed in the ICU than exacerbations managed in the general ward (see Supplementary
<figure><img src="image_4.png" /></figure>

**Figure 1** The case-crossover design. CVE, cardiovascular event. The boxes represent the time windows. The length of each time window was 4 weeks for the primary analysis and 2 or 8 weeks for the sensitivity analyses. The window columns represent the at-risk window, the wash-out window, and the four control windows. The circle indicates the index date (severe CVE), and the lightning indicates a hospitalization for an exacerbation. As the case-crossover study design provides a within-person comparison between exposure status in the at-risk time window and exposure status in the control time windows, case-patients who are always exposed or never exposed in all at-risk and control time window(s) do not contribute to the analysis ('concordant patients'). The first five case-patients are discordant and contribute to the analysis, whereas the two last case-patients are concordant.

<figure><img src="image_5.png" /></figure>

**Figure 2** Flowchart of the study population. COPD, chronic obstructive pulmonary disease; CVE, cardiovascular event; RUM, medical unit summary (French acronym Résumé d'unité médicale).
<table><caption>**Table 1** Characteristics of case-patient (case-crossover analysis) population and of the cardiovascular event at index date</caption><thead><tr><th></th><th>Case-crossover analysis population<br>(N = 9840)</th></tr></thead><tbody><tr><td>Age at CVE, mean (SD)</td><td>76.8 (10.7)</td></tr><tr><td>Age categories, n (%)</td><td></td></tr><tr><td>&lt;65 years old</td><td>1372 (13.9)</td></tr><tr><td>65-74</td><td>2546 (25.9)</td></tr><tr><td>75-79</td><td>1436 (14.6)</td></tr><tr><td>≥80</td><td>4486 (45.6)</td></tr><tr><td>Sex, male, n (%)</td><td>6496 (66.0)</td></tr><tr><td>Quintiles of deprivation index,<sup>a</sup> n (%)</td><td></td></tr><tr><td>Quintile 1 (least deprived)</td><td>1252 (12.0)</td></tr><tr><td>Quintile 2</td><td>1344 (13.9)</td></tr><tr><td>Quintile 3</td><td>1686 (17.4)</td></tr><tr><td>Quintile 4</td><td>2254 (23.3)</td></tr><tr><td>Quintile 5 (most deprived)</td><td>3142 (32.5)</td></tr><tr><td>Missing (n)</td><td>162</td></tr><tr><td>Number of hospitalizations for exacerbation of COPD within the 24 weeks before index date, n (%)<sup>b</sup></td><td></td></tr><tr><td>1</td><td>8131 (82.6)</td></tr><tr><td>2</td><td>1296 (13.2)</td></tr><tr><td>≥3</td><td>413 (4.2)</td></tr><tr><td>Characteristics of the index CVE</td><td></td></tr><tr><td>Year of CVE hospitalization, n (%)</td><td></td></tr><tr><td>2018</td><td>5157 (52.4)</td></tr><tr><td>2019</td><td>4683 (47.6)</td></tr><tr><td>Season of CVE hospitalization, n (%)</td><td></td></tr><tr><td>Spring (March-May)</td><td>3008 (30.6)</td></tr><tr><td>Summer (June-August)</td><td>2225 (22.6)</td></tr><tr><td>Autumn (September-November)</td><td>1929 (19.6)</td></tr><tr><td>Winter (December-February)</td><td>2678 (27.2)</td></tr><tr><td>Duration (in days) of the index CVE hospital stay, mean (SD)</td><td>11.7 (11.4)</td></tr><tr><td>Type of severe CVE, n (%)</td><td></td></tr><tr><td>Acute coronary syndrome, including myocardial infarction and unstable angina</td><td>1070 (10.9)</td></tr><tr><td>STEMI</td><td>249 (2.5)</td></tr><tr><td>NSTEMI</td><td>612 (6.2)</td></tr><tr><td>Unstable angina</td><td>209 (2.1)</td></tr><tr><td>Decompensated heart failure</td><td>5888 (59.8)</td></tr><tr><td>Atrial fibrillation and flutter</td><td>858 (8.7)</td></tr><tr><td>Resuscitated cardiac arrest</td><td>211 (2.1)</td></tr><tr><td>Ischaemic stroke, including transient ischaemic attack</td><td>627 (6.4)</td></tr><tr><td>Ischaemic stroke</td><td>512 (5.2)</td></tr><tr><td>Transient ischaemic attack</td><td>115 (1.2)</td></tr><tr><td>Pulmonary embolism</td><td>732 (7.4)</td></tr><tr><td>Major limb events</td><td>454 (4.6)</td></tr><tr><td>In-hospital death after a severe CVE, n (%)</td><td>950 (9.7)</td></tr></tbody></table>

COPD, chronic obstructive pulmonary disease; CVE, cardiovascular event; NSTEMI, non-ST-elevation myocardial infarction; SD, standard deviation; STEMI, ST-elevation myocardial infarction.

material online, Figure S4). Among patients for whom NSTEMI was the index CVE, many (>30%) had their last exacerbation in the 1 week prior to the NSTEMI. The proportion of patients having their last exacerbation in

the 4 weeks prior to the index CVE was highest for critical and life-threatening exacerbations (see Supplementary material online, Figures S5 and S6).

<footnote><sup>a</sup>The French deprivation index is based on the postcode of residence of the patient.<sup>22</sup> This index is constructed at the community level, as the first component of a principal component analysis of four variables: the median household income, the percentage of high school graduates in the population aged 15 years and over, the percentage of blue-collar workers in the active population, and the unemployment rate.</footnote>

<footnote><sup>b</sup>By design, all patients included in the analysis population had at least one previous hospitalization of exacerbation in the 24 weeks before index CVE.</footnote>
<table><caption>**Table 2** Case-crossover analysis of the association between a hospitalization for chronic obstructive pulmonary disease exacerbation and a cardiovascular event in the subsequent 4 weeks (vs. weeks -9 to -24)</caption><thead><tr><th></th><th>Number (%) of case-patients</th><th># of at-risk time windows with/without exacerbation<sup>a</sup></th><th># of control time windows with/without exacerbation<sup>a</sup></th><th>Discordant case-patients (N, %)</th><th>Case-crossover OR (95% CI)</th></tr></thead><tbody><tr><td>Composite outcome<sup>b</sup></td><td>9840 (100%)</td><td>3827/6013</td><td>5581/33 779</td><td>8322 (84.6)</td><td>3.03 (2.90-3.16)</td></tr><tr><td>Individual severe CVEs</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Acute coronary syndrome, including myocardial infarction and unstable angina</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>STEMI</td><td>249 (2.5%)</td><td>118/131</td><td>126/870</td><td>220 (88.4)</td><td>4.24 (3.24-5.54)</td></tr><tr><td>NSTEMI</td><td>612 (6.2%)</td><td>323/289</td><td>294/2154</td><td>539 (88.1)</td><td>5.33 (4.47-6.34)</td></tr><tr><td>Decompensated heart failure</td><td>5888 (59.8%)</td><td>2254/3634</td><td>3355/20 197</td><td>4943 (84.0)</td><td>2.96 (2.80-3.14)</td></tr><tr><td>Atrial fibrillation and flutter</td><td>858 (8.7%)</td><td>326/532</td><td>481/2951</td><td>705 (82.2)</td><td>3.03 (2.61-3.52)</td></tr><tr><td>Resuscitated cardiac arrest</td><td>211 (2.1%)</td><td>107/104</td><td>120/724</td><td>192 (91.0)</td><td>4.33 (3.24-5.79)</td></tr><tr><td>Ischaemic stroke and transient ischaemic attack</td><td>627 (6.4%)</td><td>187/440</td><td>401/2107</td><td>540 (86.1)</td><td>1.93 (1.62-2.31)</td></tr><tr><td>Pulmonary embolism</td><td>732 (7.4%)</td><td>332/400</td><td>376/2552</td><td>629 (85.9)</td><td>4.02 (3.43-4.71)</td></tr><tr><td>Major limb events</td><td>454 (4.6%)</td><td>104/350</td><td>316/1500</td><td>382 (84.1)</td><td>1.34 (1.07-1.68)</td></tr><tr><td>CVE followed by in-hospital death</td><td>950 (9.7%)</td><td>407/543</td><td>510/3290</td><td>810 (85.3)</td><td>3.60 (3.13-4.14)</td></tr></tbody></table>

CVE, cardiovascular event; STEMI, ST-elevation myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction.

## Association between exacerbation and cardiovascular event

The OR (95% CI) for the association between hospitalization for a chronic obstructive pulmonary disease exacerbation and occurrence of a CVE within the 4 following weeks (vs. 9–24 weeks) was 3.03 (95% CI, 2.90–3.16; Table 2 and Figure 3). Among each type of CVE, the greatest strength of association was for NSTEMI (OR, 5.33; 95% CI, 4.47–6.34). The level of risk of a CVE increased with increasing levels of chronic obstructive pulmonary disease exacerbation severity from OR 1.89 (95% CI, 1.77–2.02) for a severe exacerbation to OR 6.99 (95% CI, 6.09–8.03) for a life-threatening exacerbation (Figure 4A). Stratified analyses (age, sex, and season of CVE) showed that the risk of a CVE was the lowest in patients aged ≥80 years old (vs. <80) and did not differ between male and female, or according to the social deprivation index (Figure 4B). The greatest strength of association was observed for CVEs that occurred during the winter season.

## Sensitivity analyses

Supplementary material online, Tables S6 and S7 provide the results of sensitivity analyses 1 and 2, suggesting that the increase in risk is slightly more pronounced when extending the duration of time windows. This is underscored by the higher OR (95% CI) for the composite outcome at 8 weeks (OR, 3.37; 95% CI, 3.25–3.50) compared with 2 weeks (OR, 2.69; 95% CI, 2.55–2.83). Additionally, the association between a chronic obstructive pulmonary disease exacerbation and in-hospital death following a CVE was observed to be higher in the 8-week windows compared with

the 2-week windows (OR, 4.08; 95% CI, 3.60–4.61 vs. OR, 3.23; 95% CI, 2.74–3.79, respectively). Supplementary material online, Table S8 summarizes results of the primary analysis and both sensitivity analyses.

## Discussion

In this French nationwide cohort of individuals living with chronic obstructive pulmonary disease, we quantified the association of a chronic obstructive pulmonary disease exacerbation requiring hospitalization with a subsequent CVE. Results show that patients who experience exacerbations requiring hospitalization are three times more likely to have a CVE in the subsequent 4-week period than in later periods of time.

The association was observed for all types of fatal and non-fatal CVEs, in line with previous findings.²¹ These findings added further insight on the temporality and level of risks across a wider range of CVEs. We explored, for the first time, the risk of NSTEMI and STEMI separately and found that NSTEMI was more frequent than STEMI. In addition, the risk of NSTEMI tended to be greater than that of STEMI. Second, the temporality and observed risk increases were not similar across types of ischaemic events. Acute coronary syndrome and pulmonary embolism tended to occur earlier (median time to event of 31 and 34 days, respectively) than ischaemic stroke and major limb event (median time to event of 62 and 71 days, respectively). Pulmonary embolism and acute coronary syndrome were 4–4.5 times, respectively, more likely to occur following a chronic obstructive pulmonary disease exacerbation requiring hospitalization, whereas major limb events or ischaemic stroke were 1.3–1.9 times more likely, respectively. Ischaemic stroke may be mediated

<footnote><sup>a</sup>This included concordant and discordant patients.</footnote>

<footnote><sup>b</sup>Including in-hospital death.</footnote>
<figure><img src="image_6.png" /><figcaption>**Figure 3** Risk of CV events in the 4 weeks after a chronic obstructive pulmonary disease exacerbation-related hospitalization. ACS, acute coronary syndrome; AF, atrial fibrillation; CI, confidence interval; CV, cardiovascular; HF, heart failure; NSTEMI, non-ST-segment elevation myocardial infarction; OR, odds ratio; PAD, peripheral artery disease; PE, pulmonary embolism; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischaemic attack. <sup>a</sup>ORs compare the odds of a hospitalization for a chronic obstructive pulmonary disease exacerbation during the 4 weeks prior to a CV event with the odds of a hospitalization for a chronic obstructive pulmonary disease exacerbation during the 9–24 weeks prior to a CV event. <sup>b</sup>Composite endpoint includes all individual types of CV events, whether or not they were followed by in-hospital death. <sup>c</sup>In-hospital deaths were patients who died during hospitalization for a CV event. Note: By design, all confounders are taken into account with the case-crossover study design.</figcaption></figure>

by unnoticed atrial fibrillation, which may explain the relatively delayed and somewhat lower effect of chronic obstructive pulmonary disease exacerbations on stroke. Third, our findings confirm that exacerbations of chronic obstructive pulmonary disease requiring hospitalization are associated with an increased risk of decompensated heart failure.

The heightened risk observed may be partially due to treatments used for exacerbation, such as increased short-acting β-agonist use or oral corticosteroids, or in the instance of major limb events and pulmonary oedema, to the hospitalization itself. Changes in treatment during or following a hospitalization may have an effect (beneficial or not) on the cardiovascular system. However, pathophysiological mechanisms at play during chronic obstructive pulmonary disease exacerbations shed light on the risks for the cardiovascular system. Exacerbations of chronic obstructive pulmonary disease are characterized by systemic inflammation, hypoxia, and a hypercoagulable state,²⁴ all of which have the potential to trigger arterial and venous ischaemic events. The mechanisms underlying the association between exacerbation of chronic obstructive pulmonary disease and heart failure include systemic inflammation that directly inhibits myocardial contractility,²⁵ dynamic lung hyperinflation that induces intrinsic positive end-expiratory pressure,²⁶ and gas exchange abnormalities that can indirectly increase right ventricular afterload.²⁷

This first-of-its-kind study explored the impact of chronic obstructive pulmonary disease exacerbations requiring hospitalization with the risk of CVEs according to inpatient management intensity. The results demonstrate that exacerbations of all severities were associated with increased risks of CVEs. However, exacerbations requiring more intensive management were associated with higher levels of risk. In other words, there was potentially a 'severity-response' relationship between the level of chronic obstructive pulmonary disease

exacerbation severity and the strength of the association. These findings echo the impact of systemic inflammation and hypoxaemia on the cardiovascular system, with the severity of these symptoms being an important driver of ICU admission and need for ventilation. In addition, the strongest seasonal association was observed for CVEs that occurred during winter, when viral epidemics are most prevalent. Several viruses potentially involved in chronic obstructive pulmonary disease exacerbations are also risk factors of CVEs (e.g. influenza and respiratory syncytial virus).²⁸,²⁹ Possible mechanisms include direct cardiac infection and endothelial dysfunction leading to plaque destabilization and rupture and, as in chronic obstructive pulmonary disease exacerbations, hypoxaemia and systemic inflammatory responses. Our results are consistent with the fact that exacerbations of chronic obstructive pulmonary disease caused by viral infections have more severe clinical outcomes.³⁰

Another important finding is that sex or age did not modify the association, and the increased risk was similarly observed across all age groups (except ≥80 years old), suggesting that younger patients and women should also be considered at risk for a CVE.

Because we used a hospital medico-administrative database, the source population included all individuals who were hospitalized in France between 2013 and 2019 for any reason. A possible consequence of this source is the overrepresentation of more fragile individuals in whom the association may be of greater magnitude. On the other hand, the use of this large, nationwide, and exhaustive database allowed us to conduct subgroup analyses with sufficient statistical power.

The study explored the difference in risk between two periods following a hospitalized exacerbation (Weeks 1–4 and Weeks 9–24). Previous research indicated that there is an immediate increase in risk of a CVE following a hospitalized exacerbation (compared with periods outside
A

<table><thead><tr><th>Comparison</th><th>No. of at-risk windows<br>with/without an exacerbation<br>of this intensity</th><th>No. of control windows<br>with/without an exacerbation<br>of this intensity</th><th>Case-crossover<br>OR (95% CI)</th></tr></thead><tbody><tr><td>Severe vs No exacerbation</td><td>1405/6013</td><td>3227/33779</td><td>1.89 (1.77-2.02)</td></tr><tr><td>Very severe vs No exacerbation</td><td>769/6013</td><td>1186/33779</td><td>2.89 (2.63-3.17)</td></tr><tr><td>Critical vs No exacerbation</td><td>1105/6013</td><td>814/33779</td><td>6.06 (5.52-6.66)</td></tr><tr><td>Life-threatening vs No exacerbation</td><td>548/6013</td><td>354/33779</td><td>6.99 (6.09-8.03)</td></tr></tbody></table>

B

<table><thead><tr><th></th><th>Number of cases</th><th>No. of risk windows with/without exacerbation</th><th>No. of control windows with/without exacerbation</th><th>Discordant cases</th><th>Case-crossover OR (95% CI)</th></tr></thead><tbody><tr><td>Whole population</td><td>9840</td><td>3827/6013</td><td>5581/33779</td><td>8322 (84.6%)</td><td>3.03 (2.90-3.16)</td></tr><tr><td><strong>Age group (years)</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>&lt;65</td><td>1372</td><td>581/791</td><td>794/4694</td><td>1202 (87.6%)</td><td>3.30 (2.94-3.70)</td></tr><tr><td>65-74</td><td>2546</td><td>1079/1467</td><td>1393/8791</td><td>2166 (85.1%)</td><td>3.51 (3.22-3.82)</td></tr><tr><td>75-79</td><td>1436</td><td>584/852</td><td>805/4939</td><td>1223 (85.2%)</td><td>3.24 (2.89-3.63)</td></tr><tr><td>80 or more</td><td>4486</td><td>1583/2903</td><td>2589/15355</td><td>3731 (83.2%)</td><td>2.64 (2.47-2.82)</td></tr><tr><td><strong>Sex</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Male</td><td>6496</td><td>2524/3972</td><td>3718/22266</td><td>5476 (84.3%)</td><td>3.01 (2.86-3.18)</td></tr><tr><td>Female</td><td>3344</td><td>1303/2041</td><td>1863/11513</td><td>2846 (85.1%)</td><td>3.05 (2.83-3.28)</td></tr><tr><td><strong>Deprivation index</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Quintile 1 - least deprived</td><td>1252</td><td>526/726</td><td>648/4360</td><td>1043 (83.3%)</td><td>3.65 (3.23-4.13)</td></tr><tr><td>Quintile 2</td><td>1344</td><td>524/820</td><td>787/4589</td><td>1148 (85.4%)</td><td>2.95 (2.62-3.32)</td></tr><tr><td>Quintile 3</td><td>1686</td><td>644/1042</td><td>991/5753</td><td>1443 (85.6%)</td><td>2.85 (2.57-3.17)</td></tr><tr><td>Quintile 4</td><td>2254</td><td>851/1403</td><td>1240/7776</td><td>1869 (82.9%)</td><td>3.00 (2.73-3.29)</td></tr><tr><td>Quintile 5 - most deprived</td><td>3142</td><td>1217/1925</td><td>1833/10735</td><td>2683 (85.4%)</td><td>2.93 (2.71-3.17)</td></tr><tr><td><strong>Season of the index CVE</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Spring</td><td>3008</td><td>1120/1888</td><td>1697/10335</td><td>2497 (83.0%)</td><td>2.89 (2.67-3.13)</td></tr><tr><td>Summer</td><td>2225</td><td>723/1502</td><td>1519/7381</td><td>1950 (87.6%)</td><td>2.03 (1.85-2.23)</td></tr><tr><td>Autumn</td><td>1929</td><td>763/1166</td><td>1124/6592</td><td>1669 (86.5%)</td><td>2.99 (2.71-3.30)</td></tr><tr><td>Winter</td><td>2678</td><td>1221/1457</td><td>1241/9471</td><td>2206 (82.4%)</td><td>4.51 (4.14-4.91)</td></tr></tbody></table>

**Figure 4** Forest plot of the association between a hospitalized exacerbation and a subsequent severe CVE: (A) according to the intensity of inpatient care of the exacerbation; (B) according to subgroups. CI, confidence interval; COPD, chronic obstructive pulmonary disease; CVE, cardiovascular event; ICU, intensive care unit; OR, odds ratio. Exacerbations were categorized as either severe (admission in general ward), very severe (severe with acute respiratory failure), critical (admission to the ICU), or life-threatening (critical with mechanical ventilation).

exacerbations), and that the risk increase is sustained for an entire year. Our results reflect the contrast between the short-term (4 weeks) and the longer-term (up to 6 months) periods following an exacerbation and cannot be extrapolated as a full representation of the cardiovascular risk following a severe exacerbation of chronic obstructive pulmonary disease. Furthermore, results related to the longer-term analysis of CVEs should be interpreted with caution due to the case-crossover study design. In conclusion, the first month following a hospitalization for a chronic obstructive pulmonary disease exacerbation is a period of vulnerability for the cardiovascular system. Exacerbations may trigger any type of CVE—ischaemic events, arrhythmias, and heart failure decompensation—although some variability was observed in the magnitude and temporality of risk increase. Our results stress the need for immediate and sustained monitoring of patients hospitalized for an exacerbation of chronic obstructive pulmonary disease irrespective of age, sex, or the exacerbation severity to prevent a subsequent severe cardiac event. In addition, exacerbation prevention is an essential target of chronic obstructive pulmonary disease treatment.

## Supplementary material

Supplementary material is available at European Journal of Preventive Cardiology.

## Acknowledgements

Editorial support was provided by Kiley Margolis, PharmD, of Lumanity Communications Inc. under the direction of the authors in accordance with Good Publication Practice guidelines (GPP 2022) and was funded by AstraZeneca (Wilmington, DE, USA).

## Author contribution

All authors contributed to the conception or design of the work. O.B. contributed to the collection of the data. M.Z., O.B., A.R., and C.C. contributed data or analysis tools. O.B., A.R., and C.C. performed the analysis. All authors contributed to writing the paper. All authors critically reviewed the manuscript.
Funding

This study and editorial support were funded by AstraZeneca.

**Conflict of interest:** M.Z. has received fees from AstraZeneca, Chiesi, CSL Behring, GlaxoSmithKline, and Menarini. V.A. has received fees from Amarin, AstraZeneca, Boehringer-Ingelheim, NovoNordisk, and Organon. C.N., C.F.-V., K.R., and N.P. are employees of AstraZeneca and may hold stock and/or stock options in AstraZeneca. O.B., A.R., and C.C. are employees of IQVIA, which was contracted by AstraZeneca to provide research support.

Data availability

The data underlying this article were provided by the French hospital discharge database, Programme de Medicalisation des Systèmes d'Information (PMSI) to the study analytics team, for the sole purpose of the present study. Data cannot be shared for ethical/privacy reasons as per the current legal national framework in place in France (https://www.cnil.fr/en/official-texts).

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