Heightened long-term cardiovascular risks after exacerbation of chronic obstructive pulmonary disease

Key findings

In this population-based cohort study of nearly 143 000 individuals living with COPD in Canada, exacerbations of COPD were associated with an increased risk for all-cause death and hospitalisation for ACS, HF decompensation, arrhythmia and cerebral ischaemia. Among these four major CV outcomes, the risk was greatest for HF and arrhythmias, which are the outcomes least studied to date. Although the risk declined over time, it persisted up to 1 year for all the outcomes, and beyond 1 year for ACS and all-cause mortality. Similar to prior studies, the risk was markedly increased in both magnitude and duration following severe exacerbations,9–11 but even moderate exacerbations were significantly associated with adverse CV outcomes. CV events were common, as nearly half (43%) of patients exacerbated at least once during an average follow-up of 5 years.

Only two prior studies have examined HF and arrhythmia as individual outcomes in relation to exacerbations. In the Understanding potential long-term impacts on function with tiotropium (UPLIFT) trial,6 incidence rate ratios up to 180 days after an exacerbation (vs before) were notably higher for HF than for MI and stroke, supporting our findings. By contrast, in a self-controlled case series using Medicare administrative data, the magnitude of risk was comparable for HF, arrhythmias and MI.7 In UPLIFT, only moderate exacerbations served as exposure, while the US study included only patients with one single severe exacerbation, excluding frequent exacerbators. We extend these findings by evaluating both short-term and long-term risk of CV outcomes following both moderate and severe exacerbation events in a broad and generalisable population. The risk of HF and arrhythmia was markedly elevated in the initial 7 days (HRs 72.3 and 31.2, respectively) but was also very high at 8–14 days (HR 9.6 for HF).

There are several plausible explanations for the increased risk of HF decompensation following an exacerbation of COPD. Airway infection and inflammation can directly inhibit myocardial contraction, while hypoxia increases pulmonary artery pressure and right heart strain.18 19 Concurrently, dynamic hyperinflation and increased thoracic pressure may compromise ventricular filling, leading to diastolic dysfunction and potentially HF decompensation in the short and longer-term.20 Regarding cardiac arrhythmias, the biventricular impairment of preload, afterload and contractility not only reduces cardiac output but also increases atrial strain. Hypercapnia, acidosis and sympathetic activation increase automaticity and exacerbate these atrial haemodynamic effects to precipitate atrial fibrillation. Drug prescribing patterns may further compound these pathophysiological disturbances. For instance, beta-blockers may be discontinued following an exacerbation of COPD due to unfounded concerns regarding respiratory side effects.21 22

The considerable elevation in the risk of HF decompensation during the exacerbating period (1–7 days) may be partially explained by misclassification where HF decompensation is initially misdiagnosed as an exacerbation before the correct diagnosis is made, because symptoms, signs and radiological findings overlap.23 Airflow obstruction is common in decompensated HF due to interstitial and alveolar oedema compressing airways along with bronchial hyper-responsiveness. In a multinational study, only one-third of patients with COPD had HF correctly identified in the emergency department.24 In clinical practice, a diagnostic algorithm combining, for example, natriuretic peptides and cardiac imaging is essential to confirm or refute concurrent HF in patients with suspected exacerbations.25 However, misclassification would not explain our observed longer term increased risk of HF.

The association of atherosclerotic events with both moderate and severe exacerbations has been recognised for durations ranging from 30 days to 1 year.5–9 However, previous analyses have been restricted to severe patients included in clinical trials6 8 11 or using self-controlled design studies.7 9 10 We extend these findings to a large, contemporary, population-based cohort with more granular division of the early exacerbation period and longer follow-up. Similar to HF and arrhythmia, the risk was more than five-fold higher in the first 7 days compared with days 8–14. Moreover, the increased risk of ACS and all-cause death persisted beyond 1 year. The early increased risk for any CV event, particularly after severe as opposed to moderate exacerbations, likely in part reflects access to diagnostics while hospitalised or attending the emergency department (e.g., troponin, natriuretic peptide, imaging).

Acute atherosclerotic events are likely precipitated by ‘spillover’ of pulmonary inflammation into the systemic circulation.26 Inflammatory cytokines such as tumour necrosis factor-α and interleukins 1, 6 and 8 promote vascular endothelial dysfunction, leucocyte and macrophage signalling, C reactive protein and complement activation and rupture of susceptible plaques. In parallel, mediators increase fibrinogen levels, platelet activation and impair fibrinolysis. The resulting hypercoagulability leads to both thrombosis at endothelial injury and increased thromboembolic risk, particularly in patients with atrial fibrillation, highlighting the complex interplay between those mechanisms.27 The persistent, although small, long-term elevated risk beyond 1 year may suggest an acceleration of atherosclerosis, although unadjusted confounding may contribute.

Another important finding of our study is the increased risk of severe CV events and all-cause death following even a first post-diagnosis exacerbation. Exacerbation history has become a focus of attention since triple compared with dual inhaled therapy reduced the secondary endpoint of all-cause mortality in the IMPACT11 and ETHOS trials,28 whose inclusion criteria required exacerbations in addition to airflow limitation.11 Five studies have assessed CV risk—mainly MI and stroke—in patients categorised by number of exacerbations or dichotomised as <2 versus ≥2 exacerbations (‘frequent exacerbators’) in the preceding year.9–11 13 14 The associated risk was found higher,10 13 similar11 14 or lower9 in frequent compared with infrequent exacerbators. Our study further explored the effect of exacerbation history as a cumulative exposure (first, second or third exacerbation) in a broader range of CV outcomes with more granular post-exacerbation time periods. Our results do not suggest incremental risk in frequent exacerbators, highlighting the impact of exacerbation beyond the lungs even at an early stage of disease management.

Strength and limitations

The large population-based administrative health datasets included comprehensive data on hospital, ambulatory and pharmacy-level claims from all hospitals and outpatient settings in Alberta. This minimised missing information on exposure and outcome, enabled risk estimation over a long period and the differentiation between incident and prevalent patients. Compared with clinical trial data, our results are more generalisable to a broader population of real-world patients living with COPD with varying disease severity and comorbidities. Our multivariable models accounted for time-varying patient characteristics and exposure status. However, the accuracy and reporting of medical codes in claims databases can vary, due to, for example, diagnosis errors with misclassification of exposure and outcome. Unfortunately, behavioural risk factors such as smoking, diet, alcohol consumption, and body weight are not captured in the database. Unmeasured confounding may result in overestimating the strength of association.

Clinical implication

Our real-world findings of elevated risk for a broad range of cardiac events and all-cause death, persisting for 1 year or more, including first and subsequent exacerbations, emphasise the burden of cardiopulmonary risk in patients living with COPD. Patients who experience exacerbations are treated across diverse medical specialities including primary care, respirology, cardiology and internal medicine. All healthcare professionals managing patients with COPD should optimise strategies to prevent exacerbations and mitigate this heighted CV risk, which includes minimising exposure to potential triggers (e.g., clean air strategies, smoking cessation and vaccination), self-management, inhaled maintenance therapies, along with CV risk factor screening and treatment.29 30 In addition, the GOLD guidelines recommend cardiologists become familiar with the pharmacological therapies for COPD to initiate therapy in the absence of a pulmonary specialist, for example, at diagnosis.31 Once exacerbations occur, therapies and risk stratification for both cardiac and pulmonary disease should be revisited and intensified. Multidisciplinary team-based approaches are needed to address the complex interaction between lung and cardiac dysfunction. Together, these findings can help healthcare professionals identify patients at risk of CV events or death, to initiate timely preventive care and monitoring, reduce the risk of first and future exacerbations and improve patient outcomes.