Commentary

Background

Over one-third of patients with chronic obstructive pulmonary disease (COPD) die from cardiovascular disease (CVD), including atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and arrhythmia [1,2,3,4,5,6,7]. COPD and CVD have a syndemic relationship, clustering through shared risk factors and biological interactions that exacerbate the prognosis and burden of disease [8, 9]. Health systems are dominated by single-disease frameworks, siloed specialties, and fragmented systems of care [8]. While integrated cardiopulmonary care has been proposed, the concept has gained limited traction in routine clinical practice [8]. This likely reflects the historic single-organ disease control epistemology, coupled with a lack of perceived benefit and the challenges of health service reorganization. However, there is strong precedent for the evolution of inter-specialty care to follow, namely the transformation of diabetes from an endocrine-focused model to the cardio-renal-metabolic disease management paradigm [10,11,12]. In this commentary article, we draw parallels between the cardiometabolic and cardiopulmonary paradigms, and ask what evidence is needed to support the transformation.

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.

COPD and CVD Pathophysiological Mechanisms

All the major cardiovascular (CV) risk factors cluster in patients with COPD, including smoking, hypertension, dyslipidemia, diabetes, obesity, and physical inactivity [13,14,15,16]. Many of these are modifiable and thus represent opportunities for interventions that could improve patient outcomes. However, there is a growing body of evidence pointing to complex biological, physical/environmental, and socioeconomic interconnections between CVD and COPD, suggesting that the interplay between cardiopulmonary diseases cannot be attributed to interrelated risk factors alone [14].

COPD and CVD are both chronic inflammatory disorders. COPD may promote accelerated atherosclerosis through ‘spillover’ of inflammatory mediators from the lungs into the bloodstream [17], leading to changes in the microvascular environment that can result in rupture of susceptible plaques. In parallel, inflammatory mediators can promote hypercoagulability leading to increased thromboembolic risk [18], particularly in patients with pre-existing thrombotic risk factors such as atrial fibrillation (AF), highlighting the complex interplay between those mechanisms. Genetic and/or early life environmental factors in individuals with COPD may incrementally contribute to increased risk of ASCVD via pathophysiological mechanisms that remain poorly understood [19].

Similarly, there are multiple intertwined explanations for the increased risk of HF and arrhythmia in individuals with COPD. For example, myocardial contraction can be directly inhibited by airway inflammation, while pulmonary artery pressure and right heart strain can both be increased by chronic low-grade hypoxia induced by COPD [20, 21]. At the same time, dynamic hyperinflation and increased intrathoracic pressure may contribute to diastolic dysfunction and HF decompensation via impaired ventricular filling [22]. With respect to cardiac arrhythmias, the biventricular impairment of preload, afterload, and contractility both reduces cardiac output and increases atrial strain, and metabolic changes can exacerbate atrial hemodynamic effects to precipitate AF [23].

COPD is a CVD Risk-Enhancing Factor Across the Spectrum of Disease Severity

In addition to the well-defined mechanistic pathways linking COPD and CVD, multiple sectors of observational evidence suggest a significant causal relationship between the two. Reduced forced expiratory volume in one second (FEV1) in the general population is strongly associated with incident CVD and cardiovascular mortality, independent of smoking exposure and concurrent CV risk factors [24]. COPD is known to be a powerful independent predictor of incident and prevalent CVD. In a recent retrospective population-based cohort study including ∼5.8 million individuals without CVD in Canada, those with COPD had a 25% increased rate of incident CVD events after adjustment for traditional risk factors [adjusted hazard ratio (aHR) 1.25; 95% confidence interval (CI) 1.23–1.27] [25]. Similarly, in a meta-analysis of 29 datasets, patients with COPD were more likely to have prevalent CVD compared with the non-COPD population [odds ratio (OR) 2.46; 95% CI 2.02–3.00; p < 0.0001)], including a two to three times higher risk of ischemic heart disease (IHD), arrhythmia, HF, and vascular disease [26].

Once CVD is established, COPD remains an independent predictor of adverse CV events [27], irrespective of COPD severity, which is in part driven by acute exacerbations of COPD [28]. However, it must be recognized that the observational associations are significantly attenuated in studies with more comprehensive multivariable adjustment, emphasizing the importance of common risk factors in explaining the coexistence of cardio metabolic comorbidities and COPD [29,30,31,32].

The Precedent of Evolving Cardio-Renal-Metabolic Care

Although diabetes was initially considered a coronary heart disease ‘risk equivalent’ [33], subsequent meta-analyses indicated that diabetes did not convey the same magnitude of risk as established coronary disease [34]. Improvement in glycemic control certainly contributed to this reduction in risk. However, the multidisciplinary organization of care and intensive CV risk factor management in diabetes also significantly improved health outcomes prior to contemporary disease-modifying therapies [35,36,37]. Diabetes treatment initially focused on controlling hyperglycemia, with the subsequent recognition that this in turn reduced end-organ, predominantly microvascular, damage [10, 12]. The approach evolved, recognizing diabetes as a major ASCVD risk factor, and the importance of concurrent ASCVD risk factor control to improve outcomes [10,11,12, 38]. Interdisciplinary teams implemented comprehensive multi-organ disease management, including routine assessment and screening of eyes, feet, kidneys, cardiac risk factors, and disease [10,11,12]. Intensive as opposed to standard risk factor management followed (e.g., blood pressure, lipids) [10, 12] alongside systematic application of evidence-based, non-endocrine, disease-modifying treatments, including angiotensin-converting enzyme inhibitors (ACEis), angiotensin II receptor blockers (ARBs), and statins [10,11,12, 39]. Only more recently were sodium glucose transport protein 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) introduced [10,11,12, 39]. The key elements of this evolution are summarized in Table 1 and provide a framework for integrated cardiopulmonary care (Fig. 1).

Table 1 Aspects of multidisciplinary diabetes care that could be translatable to cardiopulmonary management [10,11,12, 38, 39]
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Fig. 1
figure 1

Proposed steps to adapt key concepts of integrated multidisciplinary cardiometabolic care to a cardiopulmonary disease paradigm. ACEi angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, ASCVD atherosclerotic cardiovascular disease, BP blood pressure, COPD chronic obstructive pulmonary disease, CP cardiopulmonary, CV cardiovascular, GLP-1 glucagon-like peptide 1, HF heart failure, SGLT2i sodium-glucose cotransporter-2 inhibitor, SITT single inhaler triple therapy

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ASCVD Risk is Underestimated in Patients with COPD

Primary prevention strategies are founded on risk assessment. Knowledge of the 10-year risk for ASCVD identifies patients in higher-risk groups who are likely to have greater net benefit and lower number needed to treat (NNT) from both statins and antihypertensive therapy [40]. Prevention guidelines recommend risk estimators such as the pooled cohort equations, QRISK, or SCORE2 to inform shared decision-making between clinicians and patients [41, 42]. The risk scores were developed and validated in general populations whose baseline risk is lower than selected populations, such as those with COPD. None of the CVD risk prediction tools were developed or validated in patients with COPD or include COPD as a predictor, and consequently markedly underestimate risk. In a recent retrospective cohort study, the 10-year risk of incident CVD in primary care patients with COPD was 52% higher than predicted by the QRISK score, and the discrepancy between predicted and observed CV risk was even more striking among individuals with COPD age 65 years or younger (82%) [19]. Moreover, patients with ‘borderline’ and ‘intermediate’ risk when applying current tools are considered for statin therapy in the presence of ‘risk-enhancing’ factors, which include chronic kidney disease and systemic inflammatory conditions. Notably, COPD is not currently included in guidelines as a risk-enhancing factor. Risk prediction models may significantly underestimate ASCVD risk in patients with COPD due to several factors (Fig. 2). First, there may be shared unmeasured risk factors in patients with COPD and CVD. Second, COPD may directly cause CVD through the aforementioned mechanistic pathways. Finally, models are developed for an average person in the general population but patients with COPD have higher baseline ASCVD risk.

Fig. 2
figure 2

Potential reasons why patients with COPD have higher ASCVD risk than the general population. COPD chronic obstructive pulmonary disease, CVD cardiovascular disease

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High Prevalence Yet Under-Recognition of Cardiopulmonary Disease

Screening is most cost-effective when there is a high unrecognized disease burden and absolute risk, detectable preclinical phase, accurate and acceptable tests, and disease-modifying therapies [43]. The cardiopulmonary continuum fulfills all these criteria. Through shared pathophysiology and risk factors, CVD is among the most common comorbidities in patients with COPD, and vice versa. In a systematic review and meta-analysis of 29 unique datasets, up to 64% of patients with COPD had IHD, 41% HF, 29% arrhythmias, and 13% stroke [26]. COPD is similarly prevalent in patients with CVD, although it is often undiagnosed [44]. Indeed, COPD or airflow limitation on spirometry has been reported in up to 34% of patients with IHD, 25–30% with HF, 13% with AF, and 10–12% with stroke [44,45,46]. In addition, through shared symptoms including dyspnea and exercise intolerance, CVD and COPD are also among the most unrecognized respective comorbidities. For example, undiagnosed HF is present in up to one-fifth of patients with COPD [47], and spirometry identifies undiagnosed COPD in one-quarter to one-third of patients with a broad range of CVD [48, 49].

COPD is a Risk-Enriched Population

Cardiovascular morbidity and mortality in patients with COPD is similar to that of pulmonary and cancer-related disease; overall, around one-third of deaths are attributable to the respective causes [50]. However, CVD is the leading cause of death in patients with milder COPD by Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification, while respiratory death assumes a greater proportion with increased severity of airflow obstruction [51]. This has significant implications in terms of value and cost-effectiveness of screening and treatment. Not only do patients with milder COPD represent the largest population but also the population with the greatest longevity, and therefore potential long-term gain in quality-adjusted life years.

CV Risk Exists Across the Spectrum of COPD

The fallacy of ‘stable HF’ is increasingly recognized, since, even in the absence of overt symptoms and signs, it is almost always a progressive disease with neurohormonal activation, structural remodeling, and inherent risk of decompensation and future adverse events [52]. The Canadian Cardiovascular Society guidelines for the management of HF specifically counter that the term ‘stable’ is “not considered to be clinically appropriate because of the inherent risk of future clinical events” [53]. Moreover, ‘stable’ implies good prognosis, which lowers risk perception by both patients and providers, contributing to therapeutic inertia and withholding of disease-modifying therapies. The same principles may theoretically be extended to COPD, where even patients with milder symptoms and infrequent exacerbations experience progressive lung function decline [54] and have an elevated risk of cardiovascular morbidity and mortality [51, 55].

The risk of cardiovascular events is elevated even during periods of clinically stable COPD [56, 57]. In a prospective study of 287 people with COPD who were prescribed guideline-recommended optimal COPD therapy who had not had a recent exacerbation or any prior cardiovascular event, the incidence of myocardial infarction (27%), IHD or angina (23%), peripheral artery disease requiring surgery (27%), and stroke (23%), were high over a median follow-up of 65 months [56].

Notwithstanding the need to optimize management across the spectrum of COPD severity, the risk for CV events is particularly heightened after exacerbations, making it a key driver of morbidity and mortality in individuals with COPD [28, 58,59,60]. Although the risks of myocardial infarction and stroke are highest in the first 30 days following a moderate or severe exacerbation, the period of elevated risk persists over time to at least 1 year [28, 58,59,60,61,62,63,64,65,66] (see Table S1 in the electronic supplementary material). Thus, it appears that damage from exacerbation extends beyond the lungs, and preventing exacerbations has important morbidity and mortality implications for both the pulmonary and CV systems.

Undertreatment and Opportunity to Improve CV Risk and Disease Control

Despite the high prevalence and burden of CVD in people with COPD and the availability of evidence-based primary and secondary CV risk reduction treatments [67], there is a concerning level of under treatment of CV risk factors and CVD in people with COPD [29, 68,69,70]. Recent evidence is shifting from counting comorbidities in COPD to measuring how they are monitored, treated, and controlled. In a cross-sectional study of over 30,000 patients with COPD in Canadian primary care, the major CV risk factors when defined using objective measures including laboratory results were more common than anticipated, including hypertension (52%), dyslipidemia (62%), diabetes (25%), obesity (41%), and smoking (41%) [16]. More than half of patients (54%) had a high Framingham risk score. Monitoring was suboptimal, and guideline-recommended targets for the above-mentioned risk factors were only achieved in 61%, 47%, 57%, 11%, and 12% of patients, respectively. Simple CV therapies including ACEi and statins were notably underused.

Findings are similar for secondary prevention. Patients admitted for major CV events who have COPD are significantly less likely than those without COPD to undergo invasive cardiac investigations or procedures (e.g., coronary angiography, percutaneous coronary intervention), and are less likely to be discharged on established secondary prevention medications such as antiplatelets, beta-blockers, statins, ACEis, and ARBs [29, 68,69,70]. This evidence supports the existence of a classic risk–treatment paradox in people with cardiopulmonary disease, wherein those with the greatest absolute risk of poor outcomes are the least likely to be treated with established life-saving therapies.

Undertreatment and Opportunity to Improve COPD Disease Control

In the last few decades, there has been a dramatic reduction in CVD mortality rates in Western countries, of which 47% has been attributed to the application of evidence-based medical and surgical treatments and 44% to improvements in CV risk factors, including reductions in cholesterol and blood pressure [71]. Although reductions in mortality rates due to COPD have seen a less dramatic decline owing in part to the aging population [72], mortality reduction is nonetheless an achievable goal of COPD management.

Reductions in all-cause and CV-related mortality have been demonstrated with optimal treatment of COPD that includes smoking cessation, pulmonary rehabilitation, physical activity, self-management, vaccination, and, more recently, single-inhaler triple therapy (SITT) which includes a long-acting muscarinic antagonist (LAMA), a long-acting beta-2 agonist (LABA), and an inhaled corticosteroid (ICS) [73, 74]. Two recent large, randomized, controlled trials (RCTs) compared SITT to dual therapy in nearly 19,000 patients with moderate-to-severe COPD. Over just 52 weeks in both trials, SITT reduced not only the primary endpoint of annualized rate of exacerbations but also the secondary endpoints of CV and all-cause mortality [75, 76]. These studies—ETHOS (n = 8509) and IMPACT (n = 10,355)—suggest that mortality reductions with SITT are at least as robust as smoking cessation and established cardioprotective and cardio-renal-metabolic treatments (Fig. 3). The relative NNT to prevent one death from any cause for SITT is 80 for the ETHOS study [75] and 121 for IMPACT [76]; these findings are equal or better than statin therapy in patients with IHD (NNT 164) [77] and SGLT-2is for type 2 diabetes (NNT 120) [78]. SITT is therefore a key guideline directed therapy to improve outcomes including all-cause mortality in appropriately selected patients with COPD.

Fig. 3
figure 3

Absolute reductions in all-cause mortality with SITT, smoking cessation, and secondary preventive CVD treatments [75, 78, 89]. Figure originally published by and used with permission from Dove Medical Press Ltd. International Journal of COPD 2021;16:499–517 (adapted). a Pooled analysis of adverse events leading to a fatal outcome (safety population). b On- and off-treatment deaths in post hoc analysis with additional vital status follow-up (vital status available for 99.6% of patients at nominal Week 52). c Analysis included all observed data regardless of whether patients continued to receive their assigned treatment. BDP beclomethasone dipropionate, BUD budesonide, CVD cardiovascular disease, FF fluticasone furoate, FORM formoterol, GLY glycopyrronium, ICS inhaled corticosteroid, IND indacaterol, SITT single inhaler triple therapy, UMEC umeclidinium, VI vilanterol

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Consideration of COPD Phenotypes, Endotypes, and Treatable Traits

Complex COPD phenotypes and endotypes, which have evolved into the concept of clinically relevant treatable traits as a strategy of personalized medicine [79,80,81,82], also warrant consideration within an integrated approach to cardiopulmonary care. Treatable traits in COPD may be categorized into pulmonary, extrapulmonary, and behavioral domains [79]. Pulmonary traits have traditionally been the dominant domain and include lung function/airflow limitation and airway inflammation among other factors [79, 81, 82]. Extrapulmonary traits include comorbidities and exercise intolerance, and behavioral traits include risk factors and behaviors that worsen disease symptoms and outcomes, as well as suboptimal disease self-management (e.g., poor medication adherence and administration techniques) [79]. There is benefit in implementing identification and treatment of traits into practice in patients with severe asthma and COPD, although less so for patients with mild disease at this time [79]. The magnitude of CV risk varies, although it is consistently elevated in different COPD disease phenotypes, suggesting that phenotypes and treatable traits may be helpful in developing integrated models of cardiopulmonary care [83].

As suggested by a multidisciplinary panel of experts, clinician professional development and skill enhancement, as well as funding for multidisciplinary services, could contribute to implementation of treatable traits in practice [79].

Need for Systems Change

The evidence supporting cardiopulmonary interrelationships, risk factors, and treatments with mortality benefits is incontrovertible, yet there is a dearth of evidence defining optimal care pathways for cardiopulmonary health. Dedicated RCTs to address this knowledge gap are unfortunately unlikely for several reasons, including limited funding opportunities, the challenges of testing health service interventions, and the common exclusion of patients with comorbidity from trials [84].

The care paradigm and management guidelines for diabetes shifted without dedicated trials rigorously examining different multidisciplinary models of care; therefore, the question of whether dedicated RCTs are necessary to support a shift in cardiopulmonary management is worth exploring. COPD guidance documents including the GOLD strategy acknowledge the need to recognize and address comorbidities in patients with COPD, and specifically note that CVD is a common and important comorbidity among patients with COPD, but recommendations or algorithms for screening, assessment, risk factor and disease management, and multidisciplinary care have not yet been developed [85, 86].

The central components of systems change include integrated multidisciplinary care connecting primary and specialist care, clinician and provider training, referral networks, individual case management and continuity of care, information and data sharing, care pathways and protocols, performance reporting and accountability, and education and promotion of self-management. The opportunity for improvement was highlighted in a recent multicenter, cluster-randomized, controlled trial of proactive early detection of CVD in patients with diabetes or COPD in primary care in the Netherlands [87]. A strategy including a symptom questionnaire, physical examination, N-terminal prohormone of brain natriuretic peptide, and electrocardiogram, more than doubled the number of new diagnoses of HF, AF, and coronary artery disease [87]. In the diabetes setting, interdisciplinary diabetes care teams are associated with improved health outcomes and achievement of targets for disease management [35,36,37]. Certified diabetes educators have played a key role in advancing this paradigm of patient-centered chronic cardio-renal-metabolic disease management [88]. In COPD, no such trials have been conducted. However, certified respiratory educators and respiratory technicians are well positioned to play a similar role, but education on CV risk management will be needed. Future endeavors such as expert consensus statements should aim to address gaps in our current models of care and offer guidance on how best to approach management of cardiopulmonary risk.

Conclusions

Systems change is difficult to achieve in any field, as there are numerous barriers and considerable inertia to overcome, especially when multiple disciplines are involved. Encouragingly, there is precedent for the successful implementation of systems-level change and associated improvements in morbidity and mortality by applying a multi-organ, multidisciplinary approach, as exemplified by the evolution of diabetes care. It is time for cardiopulmonary management to move beyond symptom control and reactive management to proactive prevention of exacerbations and adverse cardiopulmonary outcomes and mortality by embracing a paradigm shift to multi-organ, integrated care.