FormalPara Key Summary Points

This narrative review defines cardiopulmonary risk as the risk of serious respiratory and/or cardiovascular events in patients with chronic obstructive pulmonary disease (COPD).

Many people with COPD are at elevated cardiopulmonary risk, which may lead to early death.

Current evidence supports proactive therapeutic intervention to prevent exacerbations, reduce the risk of cardiopulmonary events and thereby reduce mortality in patients with COPD.

Reframing the management of COPD towards proactive cardiopulmonary risk reduction could transform the standard of care and, therefore, improve clinical outcomes.

Introduction

Chronic obstructive pulmonary disease (COPD) constitutes a major international health burden, with an estimated global prevalence of 10.3%, corresponding to 391.9 million cases in people aged 30–79 years [1, 2]. Furthermore, COPD is the third leading cause of death worldwide, accounting for 3.23 million deaths in 2019 [3], with annual global deaths projected to increase to over 7 million by 2060 [4].

The prevalence of diagnosed cardiovascular disease is estimated to be between 28 and 70% in patients with COPD—two- to five-fold higher than in those without COPD [5,6,7]. Collective risk factors, including but not limited to smoking and advanced age, contribute to this level of coexistence [5, 8, 9]. Yet, the association between COPD and cardiovascular disease remains even after adjustment for these factors [10]. This indicates a syndemic occurrence, where shared risk factors, fundamental pathobiological and pathophysiological interactions and social determinants of health cause an aggregation of the two diseases and exacerbate the burden and prognosis of disease [11].

Patients with COPD are at elevated risk of respiratory and cardiovascular events that may lead to early death [12,13,14,15]. Herein, for COPD, such respiratory events include exacerbations, and cardiovascular events include myocardial infarction, stroke, heart failure decompensation and arrhythmia. Respiratory and cardiovascular events are recognised as common causes of death in patients with COPD, with the predominant underlying cause of death varying according to disease severity [16]. Compared with respiratory-related deaths, cardiovascular-related deaths are more prevalent in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification mild and moderate disease (group 1 and 2), with respiratory deaths more prevalent in patients with GOLD classification severe and very severe disease (group 3 and 4) [16]. Notably, modelled projections of cause-specific deaths for patients with COPD in the UK predict higher mortality rates from cardiovascular causes than respiratory causes over a 10-year period [17].

Understanding the extent and nature of respiratory and cardiovascular events in patients with COPD and identifying approaches to reduce the risk of such occurrences is central to improving clinical outcomes. In this narrative review, we examine the current evidence regarding respiratory and cardiovascular outcomes in COPD from which we have derived the concept of cardiopulmonary risk, consider respiratory therapeutic interventions that may reduce this risk and highlight the need for a preventative approach to address cardiopulmonary risk. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Definition of Cardiopulmonary Risk

A standardised definition of cardiopulmonary risk in COPD has yet to be established. We propose a foundational basis for the use of the term cardiopulmonary risk, defined as:

‘The risk of serious respiratory and/or cardiovascular events in patients with COPD. These include, but are not limited to, COPD exacerbations, myocardial infarction, stroke, heart failure decompensation, arrhythmia and death due to any of these events.’

While myocardial infarction and stroke have standard definitions, here arrhythmia is defined as atrial and ventricular tachyarrhythmia [18,19,20].

Factors Elevating COPD-Associated Cardiopulmonary Risk

There is an expanding evidence base to suggest that COPD is an independent predictor for cardiovascular disease [6, 21,22,23]. A meta-analysis of observational studies demonstrated that patients with COPD have an increased prevalence of cardiovascular risk factors, such as hypertension and diabetes [5]. Furthermore, a population-based retrospective cohort study in Canada demonstrated that compared with patients without COPD, there was a 25% increase in the rate of major adverse cardiovascular events (MACE; hazard ratio [HR] 1.25; 95% confidence interval [CI] 1.23, 1.27) in a COPD population without a history of cardiovascular disease after adjustment for traditional cardiovascular risk factors [10]. An editorial that evaluated these data recommended that COPD itself is recognised as a distinct cardiovascular risk factor [6]. Moreover, a nationwide UK incident COPD cohort study found that the observed 10-year risk of cardiovascular disease was 52% higher than that predicted by a widely used cardiovascular risk score tool (QRISK3), indicating a considerable and distinct contribution of COPD to cardiovascular disease risk irrespective of traditional cardiovascular risk factors [24]. Thus, while the importance of traditional cardiovascular risk factors and the optimisation of treatment for cardiovascular diseases according to their guidelines is acknowledged, here we will primarily focus on the influence of symptoms and exacerbations on cardiovascular risk in COPD.

Exacerbations of COPD can irreversibly reduce lung function, accelerate the rate of subsequent exacerbations and increase the risk of death [25, 26]. Approximately 50% of patients die within 3.6 years of their first severe (hospitalised) exacerbation [26], and there is an 80% increase in the risk of death in patients who have experienced two moderate (community-treated) exacerbations within the previous year [15]. There is growing evidence of a pathobiological and pathophysiological impact of exacerbations that extends beyond the lungs. Exacerbations amplify the risk of cardiovascular events, and this risk may remain elevated for up to a year [14, 27]. A recent meta-analysis of six cohort studies amounting to 533,672 patients with COPD found that, compared with no exacerbation, the risk of myocardial infarction and stroke at between 1 and 3 months after an exacerbation was increased by over two-fold and approximately 70% respectively (risk ratio [RR] 2.43, 95% CI 1.40, 4.20; and RR 1.68, 95% CI 1.19, 2.38) [28]. The multinational EXACOS-CV programme investigated the risk of cardiovascular events following COPD exacerbations using a set of retrospective longitudinal cohort studies [29]. Data from the UK cohort showed that, compared with no exacerbation, there was a three-fold increase in cardiovascular events (defined as acute coronary syndrome, arrhythmia, heart failure, ischaemic stroke and pulmonary hypertension) within 1–14 days following an exacerbation of any severity, with the risk remaining elevated for up to and beyond 1 year [30]. This elevated risk was highest in the 2 weeks immediately after a severe exacerbation (adjusted HR 14.5; 95% CI 12.2, 17.3) and 14–30 days after a moderate exacerbation (adjusted HR 1.94; 95% CI 1.63, 2.31) [30]. Notably, when scaling the findings to the wider COPD population, approximately 28% of severe exacerbations and 22% of moderate exacerbations result in a cardiovascular event [30]. When considering individual cardiovascular components of the composite outcome, the UK cohort reported that, compared with no exacerbation, the incidence rate of heart failure was increased following an exacerbation of any severity and remained significantly elevated across the entire median follow-up period of 2.40 years (adjusted HR 2.33; 95% CI 2.24, 2.42) [30]. Similarly, in the Canadian cohort this increased risk of heart failure was observed up to 180 days following an exacerbation of any severity (adjusted HR 2.25; 95% CI 1.96, 2.59) [31]. Indeed, overall data from European and Canadian cohorts reported similar outcomes to the UK cohort, demonstrating that compared with no exacerbation, there was a heightened risk of severe cardiovascular events (defined as acute coronary syndrome, arrhythmia, heart failure and ischaemic stroke) or death within the first 7 days after a severe exacerbation (adjusted HR 15.84; 95% CI 15.26, 16.45 to HR 48.57; 95% CI 36.88, 63.96 across countries), which was sustained beyond 1 year, and for up to 6 months following a moderate exacerbation [31,32,33]. These findings are further supported by a post hoc analysis of the IMPACT study, which reported that the overall risk of cardiovascular events was higher during moderate and severe exacerbations, and remained elevated for 30 days post-exacerbation, even in patients of low cardiovascular risk [34]. Although no studies to date have investigated the association of cardiovascular events and subsequent exacerbation frequency and severity in people with COPD, the presence of cardiovascular disease in patients with COPD is reported to increase the frequency of exacerbations [35], cardiovascular-related hospitalisation and mortality [36, 37].

Prognostic markers of future exacerbations are established in the literature. A history of exacerbations is the single strongest independent predictor for future exacerbations [38], although it is important to recognise that the frequency of exacerbations may vary markedly from year to year within individual patients [39]. Complex, multivariable risk prediction models that include several prognostic risk factors have superior predictive performance compared with exacerbation history alone and may have future clinical utility [40], though such risk stratification tools are often not employed in routine clinical practice [41]. When risk is evaluated in patients with COPD, typically only the risk of an exacerbation is assessed and cardiovascular risk is overlooked [42].

Symptoms such as increased dyspnoea and frequent productive cough predict subsequent exacerbation risk. In a retrospective observational cohort study, ~ 1 in 2 patients with a Medical Research Council (MRC) grade of ≥ 3 experienced an exacerbation in the following 12 months [43]. Similarly, in a prospective observational study, patients with frequent productive cough at baseline had twice the risk of hospital admission for exacerbation within the following 12 months [13] and a 39% increased risk of a major adverse cardiovascular or respiratory event over 3 years of follow-up [44]. The totality of these cardiopulmonary interactions and events punctuates and accelerates the progression of COPD along an adverse prognostic trajectory (Fig. 1).

Fig. 1
figure 1

COPD-associated cardiopulmonary risk. Arrow type and shade indicate strength of association: strong association, with substantial supporting data (dark grey solid), emerging association, with some supporting data (dark grey dotted), suspected association, with data yet to be generated (light grey dotted). COPD chronic obstructive pulmonary disease

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Mechanisms

The precise mechanisms driving cardiopulmonary events in COPD are yet to be fully elucidated. We propose exacerbations as a foundational risk factor for respiratory and cardiovascular events that are associated with, and may amplify, underlying mechanisms already present in COPD including systemic inflammation, hyperinflation and hypoxaemia. This is based on our knowledge that lung inflammation may trigger systemic inflammation, resulting in atherothrombosis [45]. Additionally, hyperinflation hinders cardiac output and oxygenation [46, 47], and hypoxic pulmonary vasoconstriction can cause pulmonary hypertension [48], which can result in right ventricular dysfunction and reduced cardiac output [49].

Reducing COPD-Associated Cardiopulmonary Risk

Exacerbation Risk Reduction

Both mono and dual long-acting bronchodilator therapies have shown evidence of exacerbation reduction. The UPLIFT study reported a significant reduction in the risk of exacerbations with long-acting muscarinic antagonist (LAMA) monotherapy versus placebo [50], and the POET-COPD study demonstrated that LAMA monotherapy has greater efficacy versus long-acting β2-agonist (LABA) monotherapy on exacerbation prevention [51]. When evaluated in combination in the FLAME study, LAMA/LABA dual therapy was associated with a reduction in exacerbations compared with an inhaled corticosteroid (ICS)/LABA dual therapy [52]. There is also good evidence for exacerbation reduction with ICS/LABA dual therapy, which has shown greater efficacy in reducing exacerbations than LAMA/LABA dual therapy, including in the IMPACT and ETHOS studies [53, 54]. The differences observed between FLAME and the IMPACT and ETHOS studies may be explained by patient population differences, whereby IMPACT and ETHOS included patients at higher risk of exacerbations than the patient population of FLAME [52,53,54]. Overall, the benefit of ICS appears to be greatest in patients at high exacerbation risk [55].

Three different single-inhaler, fixed-dose triple-therapy combinations of ICS/LAMA/LABA have been shown to further reduce exacerbation frequency. A triple-therapy combination (fluticasone furoate/umeclidinium/vilanterol) was evaluated in the 24-week FULFIL and the 52-week IMPACT studies. FULFIL reported a significant reduction in the rate of moderate or severe exacerbations with triple therapy versus ICS/LABA [56], and IMPACT achieved its primary endpoint of reducing moderate or severe exacerbations with triple therapy versus LAMA/LABA and ICS/LABA [53]. The 24-week KRONOS and 52-week ETHOS studies evaluated the efficacy of another triple therapy (budesonide/glycopyrrolate/formoterol fumarate) versus the corresponding dual therapies [54, 57]. In KRONOS, triple therapy demonstrated a significant reduction in the rate of moderate or severe exacerbations versus LAMA/LABA [57]. Of note, this study was not enriched for patients with a history of recent exacerbations; 74.4% of the population had no documented moderate or severe exacerbations in the 12 months preceding the study [57]. Further effects of this triple therapy on the rate of exacerbations were demonstrated in the ETHOS study, which met its primary endpoint in reducing the risk of moderate or severe exacerbations versus LAMA/LABA and ICS/LABA [54]. Similarly, a significant reduction in the rate of moderate or severe exacerbations was reported in three 52-week studies, TRILOGY, TRINITY and TRIBUTE, with triple therapy (beclomethasone dipropionate/glycopyrronium/formoterol fumarate) versus the corresponding ICS/LABA dual therapy, a LAMA and a LAMA/LABA dual therapy respectively [58,59,60]. The benefit of treatment with ICS has been shown to be related to blood eosinophil count; post hoc analyses of the IMPACT and ETHOS studies reported greater exacerbation risk reduction in patients with eosinophil levels ≥ 100 cells/μl [61,62,63].

Recent real-world evidence suggests that prompt initiation of triple therapy (within 30 days post exacerbation) may further reduce the risk of future exacerbations compared with delayed (31–180 days) or very delayed (181–365 days) intervention [64, 65].

Cardiovascular Risk Reduction with Inhaled Therapy

Currently, there is a limited body of evidence for inhaled medications reducing cardiovascular events in patients with COPD. A post hoc analysis of the EUROSCOP study found that ICS monotherapy reduced the rate of ischaemic cardiac events compared with placebo [66]. Furthermore, the CLAIM study assessed the effect of dual LAMA/LABA bronchodilator therapy versus placebo on cardiac function, whereby a significant increase in left ventricular end-diastolic volume was reported for LAMA/LABA [67]. These findings are supported by a recent large observational study that reported positive effects on left atrial diameter with long-term ICS, ICS/LABA and particularly LAMA/LABA dual therapy [68]. Conversely, in the SUMMIT study, ICS/LABA had no effect on a composite cardiovascular endpoint (cardiovascular death, myocardial infarction, stroke, unstable angina and transient ischaemic attack) versus placebo in a population with moderate COPD that was enriched for cardiovascular risk [69].

In both the ETHOS and IMPACT studies, the most common cause of death was cardiovascular [70, 71], and there were numerically fewer cardiovascular deaths reported with triple therapy compared with LAMA/LABA [70, 71]. In ETHOS, a benefit of triple therapy relative to LAMA/LABA was observed for MACE [70]; notably, 42% of the patients who died in ETHOS did not experience a moderate or severe exacerbation during the study [70]. Furthermore, the ETHOS study evaluated triple therapy at two doses (low and high) of the ICS component. Both doses showed comparable effects in reducing exacerbation rates versus LAMA/LABA and ICS/LABA, but only the high-dose treatment arm reduced mortality [54]. In the pooled analysis of TRILOGY, TRINITY and TRIBUTE, there was a reduction in the risk of non-respiratory fatal events with ICS-containing triple therapy versus ICS-free treatments [72]. Together, these findings argue for a treatment benefit on cardiovascular events and death that is not exclusively related to reductions in the rate of exacerbations.

We recognise existing literature suggesting bronchodilator therapies may be associated with increased risk of cardiovascular events. A network meta-analysis reported that, compared with ICS/LABA, LAMA/LABA dual therapy and triple therapy increased MACE in patients with COPD [73]. However, the interpretation of these findings is complex. LAMA/LABA and triple therapy were not reported to increase cardiovascular risk compared with placebo, or LAMA and LABA monotherapies, and fewer cardiovascular deaths were reported for those receiving triple therapy than LAMA/LABA, suggesting a level of ICS-related cardiovascular protection [74]. Additionally, a review of the cardiovascular effects of LAMAs indicated that they do not increase the risk of severe cardiovascular adverse events when compared with other active therapies or placebo [75]. Overall, the benefits of inhaled bronchodilators alone or in combination appear to outweigh any potential risks [74]. Considering the increased risk and burden of cardiovascular events in patients with COPD, there is a need for further studies to test interventions for the prevention of cardiovascular events.

Mortality Risk Reduction

There is evidence to support a reduction in the risk of mortality with select pharmacological and non-pharmacological interventions. Among the recognised non-pharmacological interventions, smoking cessation is associated with mortality reduction estimates ranging from 32 to 84% compared with continued smoking [76], and early initiation of pulmonary rehabilitation has demonstrated a 42% reduction in mortality [77]. Furthermore, two studies have reported mortality risk reduction with long-term oxygen therapy [78, 79], and the addition of home mechanical ventilation to home oxygen therapy has demonstrated survival benefit [80].

Among pharmacological interventions, fixed-dose combination triple therapy is the only treatment with evidence supporting a reduction in all-cause mortality in patients with COPD. In an analysis of the final retrieved dataset of the IMPACT study, in which all-cause mortality was a prespecified ‘other’ endpoint, there was a reduction in mortality with triple therapy versus LAMA/LABA [53, 71]. Similarly, time to death (all cause) was evaluated as a prespecified secondary endpoint in the ETHOS study, and in an analysis of the final retrieved dataset there was a reduction in mortality with triple therapy versus LAMA/LABA [54, 70]. An analysis of pooled data from the TRILOGY, TRINITY and TRIBUTE studies comparing an ICS-containing triple therapy with ICS-free treatments showed a numerical, but not statistically significant, reduction in the risk of a fatal event [58,59,60, 72].

The effect of ICS/LABA dual therapy versus placebo on all-cause mortality was evaluated as a primary endpoint in the TORCH and SUMMIT studies [69, 81]. Both studies failed to show a statistically significant reduction in all-cause mortality; notably, both trials were unique in including patients without a recent history of exacerbations, and the SUMMIT trial only included those with moderate COPD [69, 81]. A summary of cardiopulmonary outcomes with inhaled therapies is given in Table 1.

Table 1 A summary of cardiopulmonary outcomes with inhaled therapies
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Potential Mechanisms of Cardiopulmonary Protection by Inhaled Therapies

Optimising COPD treatment may confer cardiopulmonary protection [82]. ICS could reduce inflammation in the lung [83], and bronchodilators decrease airway resistance and reduce hyperinflation, improving inspiratory capacity, reducing residual volume and potentially improving cardiac function [67, 84, 85]. Both ICS and bronchodilators may improve ventilation-perfusion matching [86,87,88], resulting in less hypoxaemia [86, 87]. These components of triple therapy have shown reductions in exacerbations, with greater benefit in combination [2].

Approaches to Cardiopulmonary Risk Management in COPD

The current approach to COPD management can be regarded as suboptimal, as it is often more reactive than proactive [89]. Moreover, there is a general perception of therapeutic inertia, defined as failure to escalate or initiate adequate therapy when treatment goals are not met [90]. This is compounded by delayed diagnosis of COPD and insufficient awareness of cardiopulmonary risk.

Although the ETHOS and IMPACT studies for triple therapy provided the first evidence for all-cause mortality reduction with a pharmacological intervention in COPD [70, 71], mortality does not currently appear to be considered a driving factor in treatment decisions for patients with COPD outside the specific parameters of long-term oxygen therapy, non-invasive lung ventilation and lung transplantation. Surveys conducted in Europe and the USA showed that prevention of mortality was not among the most common reasons cited by pulmonologists and primary care physicians for choice of prescribed maintenance therapy [91, 92]. The 2023 GOLD report highlighted that triple therapy is the only pharmacotherapy to reduce mortality in COPD [93], and the recently released Canadian Thoracic Society Guidelines went one step further by including mortality reduction in the pharmacological treatment algorithm [94]. However, fundamental change in clinical practice is still needed to ensure prioritisation of cardiopulmonary risk reduction in the management of COPD.

There is a need for the early detection and treatment of COPD in people living with cardiovascular disease and the recognition of COPD as a distinct cardiovascular risk factor. Addressing these needs will support symptom management and reduce future cardiopulmonary events through proactive escalation and optimisation of COPD therapy and management of cardiovascular conditions and risk factors. The development and validation of risk stratification tools may aid improved quantification of COPD-associated cardiopulmonary risk and allow for a more personalised approach to treatment, though such tools are often not employed in routine clinical practice. Responsibility lies with the respiratory community to continue to raise awareness of the burden of respiratory disease and its cardiopulmonary impact and to communicate the urgency for action [24]. Of note, the recent GOLD update for cardiologists sought to encourage greater consideration of COPD within cardiology and promote a multidisciplinary approach to COPD management, increasing partnership between respiratory and cardiology disciplines, as well as with primary care clinicians [89, 95].

Conclusion

In this review, we define cardiopulmonary risk as the risk of serious respiratory and/or cardiovascular events in patients with COPD. These include, but are not limited to, COPD exacerbations, myocardial infarction, stroke, heart failure decompensation, arrhythmia and death due to any of these events. We call for the consideration of cardiopulmonary risk in the management of COPD as well as increased efforts for the early identification of patients at high risk. Although further research is necessary to understand the mechanisms of cardiopulmonary risk for improvement of mitigation, evidence supports proactive therapeutic intervention to prevent exacerbations, reduce the risk of cardiopulmonary events and thereby reduce mortality in patients with COPD. Reframing COPD management towards proactive cardiopulmonary risk reduction could transform the standard and management of care and therefore improve clinical outcomes in this population.