Cardiovascular and mortality risks following COVID-19-related vs. non-COVID-19 COPD exacerbations.

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

<b>Aim:</b> Patients with Chronic Obstructive Pulmonary Disease (COPD) have an increased risk of cardiovascular disease (CVD). The aim was to investigate the association between COPD exacerbations and severe acute cardiovascular (CV) events in COPD patients with a history of CVD. <b>Methods:</b> Data from patients with COPD (≥40 years), with a hospital-based COPD clinic visit between 2010–2016 (index date) and a hospitalization for CV events (stroke, myocardial infarction) or heart failure (HF) 36 to 6 months prior to index, were linked with nationwide Danish health registries, and followed for COPD exacerbations, CV events and death. Moderate exacerbations were defined as collection of oral corticosteroids (OCS) or respiratory antibiotics; severe as hospitalizations or emergency visits. A logistic regression model was applied to estimate odds ratios (OR) with 95% CIs for CV events and death. <b>Results:</b> Of 1501 included patients, 197 (13.1%, mean age 74.1 years, 33.5% female) experienced both COPD exacerbations and a CV event during the 6 month follow-up. More than half of these had a CV event within 30 days after the COPD exacerbation. The OR of having a non-fatal CV event after a moderate exacerbation was 1.5 (95% CI: 1.0-2.2) and 6.9 (95% CI: 4.8-10.0) after a severe exacerbation. The OR of a fatal CV event was 1.4 (95% CI: 0.6-3.5) and 3.9 (95% CI: 1.6-9.1) after a moderate and severe exacerbation, respectively. <b>Conclusion:</b> Severe exacerbations were associated with increased odds of CV events, which in the majority of patients occurred within 30 days after an exacerbation. This highlights that prevention of exacerbations in patients with COPD and concomitant CVD will improve both respiratory and CV health.

EFFECT OF ACLIDINIUM BROMIDE ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND EXACERBATIONS IN PATIENTS WITH COPD AND DIFFERENT CARDIOVASCULAR RISK FACTOR LEVELS

Acute exacerbations (AEs) of COPD are increasingly recognized as episodes of heightened risk of cardiovascular events. It is not known whether exacerbation history is differentially associated with future myocardial infarction (MI) or pulmonary embolism (PE). Is the number and severity of AEs of COPD associated with increased risk of MI or PE in a real-life cohort of patients with COPD? We identified a cohort of 66,422 patients (≥ 30 years of age) with a primary diagnosis of COPD in the Swedish National Airway Register from January 2014 to June 2022, with complete data on lung function. Patients were classified by moderate (prescription of oral corticosteroids) and severe (hospitalization) exacerbations the year before index date and were followed until December 2022 for hospitalization or death from MI or PE, corresponding to > 265,000 patient-years, with a maximum follow-up time of 9 years. Competing risk regression, according to the Fine-Gray model, was used to calculate subdistribution hazard ratios with 95%CIs. Compared with no AEs of COPD in the baseline period, AE of COPD number and severity were associated with increased long-term risk of both MI and PE in a gradual fashion, ranging from a subdistribution hazard ratio of 1.10 (95%CI, 0.97-1.24) and 1.33 (95%CI, 1.11-1.60), respectively, for one moderate exacerbation, to 1.82 (95%CI, 1.36-2.44) and 2.62 (95%CI, 1.77-3.89), respectively, for two or more severe exacerbations. In a time-restricted follow-up sensitivity analysis, the associations were stronger during the first year of follow-up and diminished over time. The risk of MI and PE increased with the frequency and severity of AEs of COPD in this large, real-life cohort of patients with COPD.

This study estimated the magnitude and duration of risk of cardiovascular events and mortality following acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and whether risks varied by number and severity of exacerbation in a commercially insured population in the United States. This was a retrospective cohort study of newly diagnosed COPD patients ≥40 years old in the Healthcare Integrated Research Database from 2012 to 2019. Patients experiencing exacerbations comprised the "exacerbation cohort". Moderate exacerbations were outpatient visits with contemporaneous antibiotic or glucocorticoid administration; severe exacerbations were emergency department visits or hospitalizations for AECOPD. Follow-up started on the exacerbation date. Distribution of time between diagnosis and first exacerbation was used to assign index dates to the "unexposed" cohort. Cox proportional hazards models estimated risks of a cardiovascular event or death following an exacerbation adjusted for medical and prescription history and stratified by follow-up time, type of cardiovascular event, exacerbation severity, and rank of exacerbation (first, second, or third). Among 435,925 patients, 170,236 experienced ≥1 exacerbation. Risk of death was increased for 2 years following an exacerbation and was highest during the first 30 days (any exacerbation hazard ratio (HR)=1.79, 95% CI=1.58-2.04; moderate HR=1.22, 95% CI=1.04-1.43; severe HR=5.09, 95% CI=4.30-6.03). Risks of cardiovascular events were increased for 1 year following an AECOPD and highest in the first 30-days (any exacerbation HR=1.34, 95% CI=1.23-1.46; moderate HR=1.23 (95% CI 1.12-1.35); severe HR=1.93 (95% CI=1.67-2.22)). Each subsequent AECOPD was associated with incrementally higher rates of both death and cardiovascular events. Risk of death and cardiovascular events was greatest in the first 30 days and rose with subsequent exacerbations. Risks were elevated for 1-2 years following moderate and severe exacerbations, highlighting a sustained increased cardiopulmonary risk associated with exacerbations.

N-acetylcysteine for COPD: the evidence remains inconclusive – Authors' reply

ObjectivePatients with chronic obstructive pulmonary disease (COPD) commonly present with cardiovascular disease (CVD). We investigated the association between COPD exacerbations and major cardiovascular (CV) events in a COPD population with a history of CVD.MethodsThis population-based and register-based cohort study identified all Danish COPD patients aged ≥40 years who visited a hospital-based, pulmonary outpatient clinic for COPD between 1st January, 2010, and 31st December, 2016, from a nationwide COPD registry. Patients with a history of a major CV event 36‒6 months prior to their COPD measurement date and no CV event 6 months before this date were included. During a 6-month assessment period, the risks of a new CV event (hospitalization with fatal/non-fatal stroke, myocardial infarction, or heart failure) and moderate and severe COPD exacerbations were evaluated. Odds ratios with 95% confidence intervals for CV events and death were estimated using adjusted logistic regression models.ResultsOf the 1501 COPD patients included, 55% experienced a COPD exacerbation and 13% experienced both an exacerbation and a CV event during follow-up (6 months). The odds of a CV event were 1.5 times higher in patients with a moderate exacerbation and more than 6-times higher in those with a severe exacerbation vs patients with no exacerbation(s). The majority of CV events occurred within 30 days post exacerbation in patients who experienced both an exacerbation and a CV event. In total, 113 patients died during the study period: 28% of deaths were caused by CVD and 72% by reasons other than CVD, mostly COPD.ConclusionIn patients with known CVD, severe COPD exacerbations are associated with increased odds of major CV events that occur within 30 days post exacerbation, highlighting the need to prevent exacerbations in COPD patients with concomitant CVD to potentially improve both respiratory and CV health.

Moderate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease. To determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist (LAMA). In this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 μg (n = 1,178), or placebo (n = 1,176). Stratification was based on LAMA use. Although rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; P = 0.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants. Roflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

BackgroundThis paper reports the duration of moderate and severe exacerbations in patients with house dust mite induced allergic asthma and the impact on patients’ quality of life.MethodsPost-hoc analyses were conducted using data collected during a phase III multi-national trial (MT-04) that investigated time to moderate or severe asthma exacerbation among 485 patients during withdrawal from inhaled corticosteroids. Patient diaries were analysed to ascertain duration of exacerbations. The impact on patients’ quality of life was measured by calculating utilities for five health states using the EuroQol-5 Dimension (EQ-5D-3L) and Asthma Quality of Life Questionnaire (AQL-5D). A regression analysis predicted the disutility of moving from ‘well controlled asthma’ to the other four health states: ‘partially controlled asthma’, ‘uncontrolled asthma’, ‘moderate exacerbation’ and ‘severe exacerbation’.ResultsTwo hundred four patients experienced exacerbations. Moderate and severe exacerbations involved statistically significant reductions in lung function compared to the constant peak expiratory flow observed for patients without exacerbations. Lung function decline occurred for 28 days, decreasing approximately 14 days before an exacerbation followed by a return to baseline over 14 days. Asthma symptoms, the use of short-acting β2-agonists, and frequency of nocturnal awakening all increased, starting 10–14 days before an exacerbation, and returned to baseline within 10–28 days following exacerbations. Compared to ‘well controlled asthma’, the disutility of having a ‘moderate exacerbation’ ranged from − 0.0834 to − 0.0921 (EQ-5D-3L) and from − 0.114 to − 0.121 (AQL-5D); and of having a ‘severe exacerbation’ from − 0.115 to − 0.163 (EQ-5D-3L) and from − 0.153 to − 0.217 (AQL-5D), depending on the length of the observation period.ConclusionsThe impact of moderate and severe exacerbations in house dust mite induced allergic asthma extends 14 days before and 28 days after the peak exacerbation event. The impact of exacerbations on patients’ health-related quality of life (HRQoL) continues long after their occurrence.

Rationale : COPD exacerbations are associated with elevated risk for further COPD exacerbations and increased morbidity and mortality. Patients with COPD and concurrent asthma may have higher risk of exacerbations than those with COPD or asthma alone; it is unknown whether timely intervention with single-inhaler triple therapy would have benefits on their exacerbation risk. This study investigated whether prompt initiation of Budesonide/Glycopyrrolate/Formoterol Fumarate (BGF) after an exacerbation among patients with COPD and asthma is associated with reduced subsequent COPD exacerbations compared to delayed and very-delayed initiation strategies. Methods: The MITOS EROS+CP (US) study was a retrospective analysis of patients with COPD from the United States using the Inovalon More2 Registry and Medicare Fee-for-Service claims; this analysis focused on a sub-group of patients with concurrent asthma diagnosis (COPD+asthma). Patients were aged ≥40 years, with 12-months baseline history, initiating BGF therapy between July 2020-May 2023, and within 1 year of a qualifying COPD exacerbation: (a) ≥1 severe exacerbation, (b) ≥2 moderate exacerbations without prior inhaled maintenance therapy or (c) ≥1 moderate exacerbation while on prior therapy. The first observed qualifying exacerbation event defined the index date. Negative binomial regressions were used to assess the adjusted risks for subsequent exacerbations by initiation group: prompt (≤30 days), delayed (31-180 days), and very-delayed (181-365 days); adjustments were made for age, gender, race, comorbidity, payer group, index event type, and baseline exacerbations. Results: 8837 patients with COPD+asthma were identified; 1090 (12.3%) prompt, 3292 (37.3%) delayed, and 4455 (50.4%) very-delayed initiators. Overall, mean age was 66.1 years, 72.0% were female, and mean follow-up was 479.3 days. Crude post-index exacerbation rates per person-year (95% CI) were 1.38 (1.30-1.45) for prompt compared to 1.90 (1.85-1.94) and 2.48 (2.45-2.52) for delayed and very-delayed initiators, respectively (Figure 1). After adjustments, prompt initiators had 20% and 25% lower incidence of subsequent exacerbations compared to delayed (IRadj: 0.80 [0.75-0.85]) and very-delayed initiators (IRadj: 0.75 [0.71-0.80]) (Figure 1). Conclusion: Among patients with COPD who have a concurrent diagnosis of asthma, promptly initiating BGF following a moderate or severe COPD exacerbation was associated with a 20% and 25% lower annualized rate of subsequent exacerbations compared to delayed and very delayed BGF initiation, respectively. Proactive use of BGF even after a single moderate COPD exacerbation among patients with COPD and asthma, who have higher disease burden than either condition by itself, may be warranted to prevent further exacerbations and reduce their morbidity.

Although recently introduced in the pharmacological treatment algorithm of chronic obstructive pulmonary disease (COPD), there is a need for more data supporting the use of blood eosinophil counts as a biomarker to guide inhaled corticosteroids (ICS) therapy. The aim of this study was to evaluate the risk of moderate and/or severe exacerbations and all-cause mortality in a large primary care population after withdrawal of ICS compared to continued users stratified by elevated blood eosinophil counts. In this population based cohort study, we used data from the Clinical Practice Research Datalink (CPRD) in the United Kingdom. We included subjects’ aged 40 years or more who had a diagnosis of COPD. We excluded subjects with a history of asthma, pulmonary fibrosis, cardiac arrhythmia and bronchiectasis, COPD exacerbations occurring within 6 weeks prior to index date, or with a myocardial infarction within 3 months prior to index date. Continuous users were subjects who received their most recent ICS prescription within 3 months before the start of an interval. ICS withdrawals were those who discontinued ICS for more than 3 months. We evaluated the risk of moderate and/or severe exacerbations and all-cause mortality among subjects with various blood eosinophil thresholds who withdrew from ICS compared to continuous ICS users with elevated blood eosinophil levels using Cox regression analysis adjusted for potential confounders. We identified 48,157 subjects diagnosed with COPD between 1 January 2005 to 31 January 2014. Withdrawal of ICS was not associated with an increased risk of moderate-to-severe exacerbations among subjects with absolute blood eosinophil counts ≥0.34 × 109 cells/L [adjusted hazard ratio (adj. HR) 0.72; 95% confidence interval (CI) 0.63–0.81] or relative counts ≥ 4.0% (adj. HR 0.72; 95% CI: 0.66–0.78). Similarly, withdrawal of ICS was not associated with an increased risk of severe exacerbations among subjects with absolute blood eosinophil ≥0.34 × 109 cells/L (adj. HR 0.82; 95% CI: 0.61–1.10) or relative blood eosinophil counts ≥4.0% (adj. HR 0.80; 95% CI: 0.61–1.04). No increased risk of all-cause mortality was observed among subjects who withdrew from ICS irrespective of elevated absolute or relative blood eosinophil counts. In a real-world primary care population, we did not observe an increased risk of moderate and/or severe COPD exacerbations or all-cause mortality among subjects with eosinophilia who withdrew their use of ICS.

Rationale : Timely initiation of therapy can reduce risks of COPD exacerbations. This study investigated whether prompt initiation of single-inhaler triple therapy Budesonide/Glycopyrrolate/Formoterol Fumarate (BGF) after a COPD exacerbation is associated with a reduction in subsequent COPD exacerbations and cardiopulmonary events compared to delayed and very delayed initiation strategies. Methods: The MITOS EROS+CP (US) study was a retrospective analysis of patients with COPD from the United States between July 2020-May 2023 using the Inovalon More2 Registry and Medicare Fee-for-Service claims, focusing on BGF initiators and a sub-group of patients who escalated from prior dual therapy (‘dual escalators’). Patients included were aged ≥40 years, with 12-months baseline history and who initiated BGF therapy within 1 year of a qualifying COPD exacerbation: (a) ≥1 severe exacerbation, (b) ≥2 moderate exacerbations without prior inhaled maintenance therapy or (c) ≥1 moderate exacerbation while on prior therapy. The first observed qualifying exacerbation defined the index date. Negative binomial regressions were used to assess the adjusted risks for subsequent exacerbations and nonfatal severe cardiopulmonary events by initiation group: prompt (≤30 days), delayed (31-180 days), and very delayed (181-365 days). Adjustments were made for age, gender, race, comorbidity, payer group, index event type, and baseline exacerbations or cardiopulmonary events (severe exacerbations and cardiovascular-related hospitalizations). Results: 25,603 patients with COPD were identified; 15,023 (58.6%) escalated from prior dual therapy. Overall, 14.8% were prompt, 37.7% delayed, and 47.5% very delayed initiators; mean age was 60.3 years and 64.3% were female, and mean follow-up was 462.2 days. Dual escalators had more very delayed initiators (51.9%). After adjustments, prompt patients had 26% (adjIRD: 0.74 [0.72-0.77]) and 31% (adjIRVD: 0.69 [0.67-0.72]) lower incidence of subsequent exacerbations and 16% (adjIRD: 0.84 [0.77-0.91]) and 17% (adjIRVD: 0.83 [0.77-0.89]) lower incidence of cardiopulmonary events, with fewer severe exacerbations and CV events, compared to delayed and very delayed initiators. Among the 10,630 cardiopulmonary events observed, 63% were cardiovascular-related. Dual escalators demonstrated similar results for both outcomes favoring prompt initiation (Table 1). Conclusion: Promptly initiating BGF following a moderate or severe exacerbation was associated with a 26% and 31% lower annualized rate of subsequent exacerbations and 16% and 17% lower annualized rate of cardiopulmonary events compared to delayed and very delayed groups. Results were similar among dual escalating patients. Proactive use of BGF, even among patients escalating from dual therapy, is associated with reduced risk of subsequent exacerbations and cardiopulmonary events among patients with COPD.

Background and Aims:Exacerbations of chronic obstructive pulmonary disease (COPD) drive disease progression and can lead to an accelerated decline in lung function and a burden on healthcare systems. The retrospective, observational cohort Study on HEalthcare Resource utiLization related to exacerbatiOns in patients with COPD (SHERLOCK; D5980R00014) evaluated the associations between exacerbation history and rates of subsequent COPD exacerbations in primary care patients from the National Health Service in Greater Glasgow and Clyde, United Kingdom.Methods:Patients were stratified into four groups according to exacerbation history in the year before the index date: Group A (no exacerbations), Group B (1 moderate exacerbation only), Group C (1 severe exacerbation only), and Group D (⩾2 moderate or severe exacerbations). The frequencies of moderate and/or severe exacerbations were recorded over 36 months of follow-up and compared with reference Group A, using generalized linear models.Results:Over 36 months of follow-up, the adjusted rate ratios (RRs, 95% confidence interval) of moderate or severe exacerbations relative to Group A were 1.60 (1.53, 1.67), 1.75 (1.50, 2.04), 1.61 (1.54, 1.68), and 3.61 (3.48, 3.74) for Groups B, C, B + C, and D, respectively. Compared with Group A, patients in Group C exhibited an increased rate of moderate (RR, 1.58 (1.35, 1.85)) and severe exacerbations (RR, 3.13 (2.20, 4.46)).Conclusion:SHERLOCK highlights that even one moderate exacerbation increases the risk for subsequent exacerbations compared with having no recent prior exacerbations. Reviewing recent exacerbation history to ascertain future exacerbation risk and inform COPD management may reduce hospitalizations and improve patient outcomes.

In the InforMing the Pathway of COPD Treatment (IMPACT) trial, single-inhaler fluticasone furoate (FF) /umeclidinium (UMEC) /vilanterol (VI) significantly reduced severe exacerbation rates and all-cause mortality (ACM) risk versus UMEC/VI among patients with chronic obstructive pulmonary disease (COPD). This post hoc analysis aimed to define the risk of ACM during and following a moderate/severe exacerbation, and further determine the benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI using a cardiopulmonary composite adverse event (AE) endpoint. The 52-week, double-blind IMPACT trial randomized patients with symptomatic COPD and ≥1 exacerbation in the prior year 2:2:1 to once-daily FF/UMEC/VI 100/62.5/25mcg, FF/VI 100/25mcg, or UMEC/VI 62.5/25mcg. Post hoc endpoints included the risk of ACM during, 1-90 and 91-365 days post moderate or severe exacerbation and time-to-first cardiopulmonary composite event. Of the 10,355 patients included, 5034 (49%) experienced moderate/severe exacerbations. Risk of ACM was significantly increased during a severe exacerbation event compared with baseline (hazard ratio [HR]: 41.22 [95% confidence interval (CI) 26.49-64.15]; p<0.001) but not significantly different at 1-90 days post-severe exacerbation (HR: 2.13 [95% CI: 0.86-5.29]; p=0.102). Moderate exacerbations did not significantly increase the risk of ACM during or after an exacerbation. Cardiopulmonary composite events occurred in 647 (16%), 636 (15%), and 356 (17%) patients receiving FF/UMEC/VI, FF/VI, and UMEC/VI, respectively; FF/UMEC/VI significantly reduced cardiopulmonary composite event risk versus UMEC/VI by 16.5% (95% CI: 5.0-26.7; p=0.006). Results confirm a substantial mortality risk during severe exacerbations, and an underlying CV risk. FF/UMEC/VI significantly reduced the risk of a composite cardiopulmonary AE versus UMEC/VI.

BackgroundPeople living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations.MethodsPersons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1–7, 8–14, 15–30, 31–180 and 181–365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome.Results8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8–20.0) in days 1–7 to 1.3 (1.0–1.8) in days 181–365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3–4.8) in days 1–7 to 1.6 (1.3–2.1) in days 31–180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9–64.0) in days 1–7 down to 1.6 (1.0–2.6) in days 181–365]. Increase in risk concerned all categories of severe CV events.ConclusionsAmong incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.