
==== Front
Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

39133888
202407-1320ST
10.1164/rccm.202407-1320ST
American Thoracic Society Documents
A Research Agenda to Improve Outcomes in Patients with Chronic Obstructive Pulmonary Disease and Cardiovascular Disease: An Official American Thoracic Society Research Statement
https://orcid.org/0000-0002-2872-3388
Myers Laura C.
Quint Jennifer K.
https://orcid.org/0000-0003-1286-2014
Hawkins Nathaniel M.
Putcha Nirupama
https://orcid.org/0009-0001-0770-8138
Hamilton Alan
Lindenauer Peter
https://orcid.org/0000-0001-9612-5454
Wells J. Michael
Witt Leah J.
Shah Sagar P.
Lee Todd
https://orcid.org/0000-0002-3650-3705
Nguyen Huong
Gainer Caroline
Walkey Allan
https://orcid.org/0000-0003-3646-7828
Mannino David M.
https://orcid.org/0000-0002-8418-4497
Bhatt Surya P.
Barr R. Graham
Mularski Richard
Dransfield Mark
https://orcid.org/0000-0003-0643-1859
Khan Sadiya S.
https://orcid.org/0000-0002-0246-594X
Gershon Andrea S.
https://orcid.org/0000-0002-0770-7653
Divo Miguel *
https://orcid.org/0000-0001-9961-4878
Press Valerie G. *on behalf of the American Thoracic Society Assembly on Behavioral Science and Health Services Research

Correspondence and requests for reprints should be addressed to Laura C. Myers, M.D., M.P.H., Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612. E-mail: laura.c.myers@kp.org.
* Co–senior authors.

01 9 2024
15 9 2024
01 9 2024
210 6 715729
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ You may print one copy of this document at no charge. However, if you require more than one copy, you must place a reprint order. Domestic reprint orders: amy.schriver@sheridan.com; international reprint orders: louisa.mott@springer.com.

Background

Individuals with chronic obstructive pulmonary disease (COPD) are often at risk for or have comorbid cardiovascular disease and are likely to die of cardiovascular-related causes.

Objectives

To prioritize a list of research topics related to the diagnosis and management of patients with COPD and comorbid cardiovascular diseases (heart failure, atherosclerotic vascular disease, and atrial fibrillation) by summarizing existing evidence and using consensus-based methods.

Methods

A literature search was performed. References were reviewed by committee co-chairs. An international, multidisciplinary committee, including a patient advocate, met virtually to review evidence and identify research topics. A modified Delphi approach was used to prioritize topics in real time on the basis of their potential for advancing the field.

Results

Gaps spanned the translational science spectrum from basic science to implementation: 1) disease mechanisms; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) clinical trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac and pulmonary rehabilitation; and 10) health equity. Seventeen experts participated, and quorum was achieved for all votes (>80%). Of 17 topics, ≥70% agreement was achieved for 12 topics after two rounds of voting. The range of summative Likert scores was −15 to 25. The highest priority was “Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements.” Health equity was identified as an important topic that should be embedded within all research.

Conclusions

We propose a prioritized research agenda with the purpose of stimulating high-impact research that will hopefully improve outcomes among people with COPD and cardiovascular disease.

Keywords

chronic obstructive pulmonary disease
cardiovascular disease
research priorities
==== Body
pmcContents

Overview

Introduction

Methods Committee Composition

Literature Search and Review of Existing Evidence

Meetings and Modified Delphi Rounds

Document Development

Results

Discussion

Conclusions

Overview

People with chronic obstructive pulmonary disease (COPD) often have comorbid cardiovascular disease and die of cardiovascular-related causes. Beyond smoking as a shared risk factor, complex pathophysiologic mechanisms are at play between the lungs and the heart. Because people with comorbid cardiovascular conditions are often excluded from COPD trials, our ability to provide evidence-based care to these individuals is hindered. Our goal was to summarize existing evidence and use consensus-based methods to prioritize a list of research topics related to the diagnosis and management of patients with COPD and common cardiovascular diseases, such as heart failure, atherosclerotic cardiovascular disease, and atrial fibrillation. After performing a literature search on comorbid COPD and cardiovascular disease, we convened an international, multidisciplinary committee including a patient member and experts in the field to review the evidence and identify research gaps. • The research gaps spanned the following 10 domains across the translational science spectrum from basic science to implementation research: 1) mechanisms of disease; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) clinical trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac and pulmonary rehabilitation; and 10) health equity.

• A modified Delphi approach was used to prioritize the research topics in real time on the basis of their potential to advance the field and ultimately improve the lives of patients with COPD and comorbid cardiovascular disease. The topic that was voted to be top priority was “Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements,” such as real-world effectiveness trials of the polypuff or polypill in the COPD patient population with concurrent cardiovascular disease. In addition, health equity was emphasized by the panel as cross-cutting all the domains and an important gap that should be embedded within all research proposed by the panel.

This research statement sets forth a prioritized research agenda that is based on expert opinion with the purpose of stimulating high-impact research for the optimal management of COPD and cardiovascular disease.

Introduction

The burden of COPD is significant, affecting 479 million individuals worldwide in 2020 (1). The global burden of COPD is projected to increase by 23% between 2020 and 2050 (1). Cardiovascular disease is a leading cause of death worldwide (2). Comorbid cardiovascular conditions are common in patients with COPD (3–9). Compared with the general public, patients with COPD are ∼2.5 times more likely to have cardiovascular disease (7). Across cohorts, the prevalence of heart failure (7–42%), ischemic cardiovascular disease (2–18%), and arrhythmia (3–21%) is consistently high in people with COPD (3–9). Approximately 35% of deaths among patients with COPD are attributed to cardiovascular events (10–12), irrespective of airflow obstruction (13), which means that optimally treating cardiovascular disease in patients with COPD could have significant benefit at the population level.

There is growing recognition of the importance of multimorbidity, which is a shift in clinical medicine and patient care (14), that is, treating the whole patient rather than the individual diseases in isolation. COPD and cardiovascular diseases are intertwined in many complex ways (4, 15–17), including the following: 1. Both share smoking as a significant risk factor (18). Smoking activates the same underlying inflammatory pathways (TNF-α, IL-6, CRP, etc.) and aging pathways (telomere shortening, cellular senescence) in COPD and cardiovascular disease (19, 20). Smoking leads to acute inflammation, oxidative stress, protein imbalance, elastin degradation, hypoxia or hypercapnia, endothelial dysfunction, thrombogenicity, atherosclerosis, and arterial stiffness (19, 21, 22), resulting in direct damage to both lung and heart tissue.

2. The two organs are interconnected anatomically and physiologically, as the pulmonary vasculature is situated between the ventricles, resulting in closely tied structure and function (23). It is well established that hypoxemia induces vasoconstriction in the arteries in the lung, leading to chronic pulmonary hypertension (type 3) and right heart failure. As the right heart chamber and muscle enlarge, there is ventricular interdependence, leading to the obstruction of left ventricular filling and poor cardiac output. This causes pulmonary vascular congestion and pulmonary congestion, which worsen respiratory failure. This interconnection between the lung and heart is cyclical and reciprocal. A more recent example is preliminary evidence showing that certain cardiovascular parameters (oxygen pulse and pulse pressure) improve after lung volume reduction surgery in emphysema (24).

3. Exacerbations in one organ system can perturb the other organ system. The risk of cardiovascular events dramatically increases in the 30 days after a COPD exacerbation and persists up to one year (25–28), which suggests that systemic inflammation caused by one disease process (COPD) directly affects other organs, such as the heart.

4. Inactivity due to fatigue or hypoxemia from COPD can increase the risk of coronary artery disease.

5. Medications to treat one condition can negatively affect the other organ system (19, 29). For example, on the pulmonary side, treating patients with COPD exacerbation with azithromycin is associated with a small increase in the risk of cardiovascular death compared with no antibiotics or amoxicillin, which was most pronounced for patients at highest risk of cardiovascular events (30).

6. The presence of a comorbidity might alter clinicians’ risk:benefit ratio to provide evidence-based care for the first condition. Patients with COPD and heart failure might not be given β-blockers, although it is an evidence-based indication for a β-blocker, out of concern for bronchoconstriction, even though the absolute risk with cardioselective (B1) β-blockers is inconsequential (31–36). At the population level, this practice pattern of not receiving guideline-concordant care for heart failure likely contributes to excess deaths and represents a translation gap.

7. It can be diagnostically challenging to differentiate COPD from cardiovascular disease, because they present with similar symptoms, such as shortness of breath and fatigue, in both the acute and chronic states (15, 37, 38). Without a thorough review of systems, physical examination, laboratory workup (brain natriuretic peptide and differential diagnosis), patients with COPD with worsening shortness of breath might be treated with escalating bronchodilator therapy, when they are in fact developing heart failure and/or arrhythmias. Similarly, patients with COPD who present to acute care with shortness of breath and wheezing may be treated with nebulizers and antibiotics because the suspicion for COPD exacerbation is so high, whereas pulmonary vascular congestion might in fact be the driving etiology.

These complexities have limited our ability to affect the disease course of COPD. Risk factors for cardiovascular disease are well known and modifiable (cholesterol, blood pressure control, etc.), and mortality from ischemic heart disease has trended downward over time. Meanwhile, mortality from COPD has not (39). Trials to treat patients with COPD using new combinations of inhalers have not decreased mortality, which could be because patients are not being treated optimally for all of their comorbid conditions. Understanding the complex interplay between the heart and lungs could open new avenues for population health management and new therapeutics (40). After performing a literature review, we used consensus-based methods to prioritize research topics related to the diagnosis and management of common comorbid cardiovascular conditions that exist in patients with COPD. For the purposes of this workshop, we defined “cardiovascular disease” as heart failure, atherosclerotic cardiovascular disease, and atrial fibrillation, using the clinical framework of pump, ischemia, and rhythm. This research statement is a call to action with the goal of expediting research that will have the greatest impact on patients with COPD and cardiovascular disease.

Methods

Committee Composition

This project was approved by the American Thoracic Society (ATS) Program Review Subcommittee. The co-chairs (L.C.M., M.D., V.G.P.) convened a multidisciplinary, international committee of members representing internal medicine, pulmonology, cardiology, geriatrics, nursing, pharmacy, drug development, quality improvement and policy, learning health systems, patient experience, and patient advocacy. Members represented urban and rural healthcare settings, academic and nonacademic institutions, and professional societies. Before confirming the final roster, potential conflicts of interest were disclosed and managed per the policies and procedures of the ATS.

Literature Search and Review of Existing Evidence

The lead co-chair (L.C.M.) performed a literature search with help from a Kaiser Permanente librarian. The search methodology is described in Figure E1 in the data supplement. Using Medical Subject Headings “Cardiovascular Diseases/therapy”(MAJR) AND “Pulmonary Disease, Chronic Obstructive/therapy”(MAJR) together with filters for adults ≥18 years of age and published in the past 5 years, separate queries were done for articles related to 1) diagnosis, 2) management, and 3) rehabilitation. Articles were reviewed to inform the agenda for Day 1.

Meetings and Modified Delphi Rounds

Two separate meetings were held virtually (September 5, 2023, and September 27, 2023). The first day was a 6-hour session comprising six presentations and four discussions that were led by experts in the field. Presentations focused on existing literature and identifying existing gaps related to three cardiovascular conditions common in COPD (heart failure; atherosclerotic cardiovascular disease, which includes vessels in the heart, brain, and periphery; and atrial fibrillation). These three conditions were chosen using the clinical framework of “cardiovascular pump, ischemia, rhythm.” Content and discussion spanned the outpatient to inpatient care spectrum and addressed the complex relationships that exist between COPD and cardiovascular disease. Discussion of drugs were done at the class level. A patient representative with COPD and cardiovascular disease (C.G.) participated and provided the patient perspective. She stressed the importance of developing new technologies (drugs and devices) to facilitate the care and day-to-day management of COPD, streamline the care of patients with COPD who have multimorbidity to prevent siloed management among specialists, limit polypharmacy, decrease cost for patients, and improve adherence to guideline-based therapies. Twenty-two experts attended the first session. The audio file was transcribed using the TranscribeMe service and loaded into a word cloud that examined the frequency of words and their proximity to one another. The co-chairs generated a list of 10 domains of gaps from Day 1’s discussion that mapped onto the framework for the translational science spectrum, courtesy of the National Heart, Lung, and Blood Institute (41).

The second day was a 2-hour session to review the proposed list of research topics that were generated by the co-chairs and to perform a modified Delphi process in real time to prioritize the list (42, 43). Eighteen experts attended the second session. Seventeen of the 18 experts voted in all polls; the remaining person (co-chair V.G.P.) facilitated the Delphi rounds and was reserved to break a tie (if needed). Participants were given an opportunity to fully read the list of research topics before voting to prevent bias based on the order in which topics were listed. For each topic, participants were asked whether the topic should be considered a top priority, which was defined as holding significant potential for advancing the field and ultimately improving the lives of patients with COPD and cardiovascular disease. Participants voted via Zoom poll using a five-point Likert scale (strongly disagree, disagree, neutral, agree, and strongly agree). Participants were limited to using a vote of strongly agree or agree a maximum of five times to facilitate generating a prioritized list with a gradient. The anonymized results were displayed in real time after each round. If ≥70% agreement was not achieved after the first round (agreeing that the topic is either a priority or not a priority), a short (<10-min) discussion ensued to highlight key strengths and limitations of the proposed topic. A second and final poll was then launched. Additional details about the polling are provided in the data supplement.

Document Development

A co-chair (M.D.) performed the data analysis. The summative Likert score from the final round was calculated, where strongly disagree was assigned a score of −2, disagree was assigned a score of −1, neutral was assigned a score of 0, agree was assigned a score of +1, and strongly agree was assigned a score of +2. The final list of prioritized topics was then ordered by the summative Likert score from the final round. Results were sent to participants electronically for feedback. The lead co-chair (L.C.M.) drafted the initial version of the manuscript, which was then circulated to the full committee and iteratively revised. The ATS Board of Directors approved the final document. This document does not include clinical treatment recommendations.

Results

Committee members were diverse in terms of sex, race and ethnicity, geographic location, medical specialty, clinical discipline, research experience/expertise, and perspective (Table 1). The literature search for COPD and cardiovascular disease yielded 97 articles (34 for diagnosis, 43 for management, and 20 for rehabilitation). The key citations that informed Day 1’s content are highlighted in Table 2.

Table 1. The International Multidisciplinary Committee for Prioritizing Research Topics in the Field of Chronic Obstructive Pulmonary Disease and Cardiovascular Disease

Committee Member	Institution	Role	Area of Expertise	
Laura Myers, M.D.	Kaiser Permanente Northern California	Co-chair, host	Overlap of COPD and cardiovascular disease, COPD readmissions, patient quality, safety, and policy	
Valerie G. Press, M.D., M.P.H.	University of Chicago	Co-chair, Delphi facilitator	COPD medications, treatment adherence, health literacy, COPD readmissions	
Miguel Divo, M.D., M.P.H.	Harvard University	Co-chair, speaker, data analyst	COPD and multimorbidity	
Jennifer Quint, M.D., Ph.D.	Imperial College London, United Kingdom	Member, speaker	Epidemiology of COPD and cardiovascular disease	
Peter Lindenauer, M.D.	Baystate Health	Member, speaker	COPD and pulmonary rehabilitation	
Nirupama Putcha, M.D., M.H.S.	Johns Hopkins Medicine	Member, speaker	Multimorbidity, health disparities	
Alan Hamilton, Ph.D.	COPD Foundation	Member, speaker	Pharmacological and nonpharmacological interventions for COPD, behavior change for patients with multimorbidity, regulatory drug approval	
Nathaniel M. Hawkins, M.D., M.P.H.	University of British Columbia, Canada	Member, speaker	Heart failure, cardiac arrhythmias, comorbidities	
Caroline Gainer	Patient	Member, speaker	Patient experience and advocacy	
J. Michael Wells, M.D., M.S.P.H.	University of Alabama at Birmingham	Member, discussion moderator	COPD and pulmonary vascular disease; mechanisms of inflammation and vascular remodeling	
David Mannino, M.D.	COPD Foundation	Member, discussion moderator	Epidemiology of COPD, environmental exposures, inflammation	
R. Graham Barr, M.D., Dr.P.H.	Columbia University	Member, discussion moderator	Prospective cohort studies, epidemiology, cardiopulmonary interactions	
Mark Dransfield, M.D.	University of Alabama	Member, discussion moderator	COPD, clinical trials, mechanisms of disease, health system leadership, leadership in multicenter randomized clinical trials	
Sadiya S. Khan, M.D., M.Sc.	Northwestern University Feinberg School of Medicine	Member	Preventive cardiology, screening for comorbidities, epidemiology, prospective cohort studies, member of the American Heart Association	
Sagar Shah, M.D.	Kaiser Permanente Northern California	Member	General internal medicine, referrals to specialists, polypharmacy	
Allan Walkey, M.D.	University of Massachusetts	Member	COPD, practice patterns, health services research, learning health systems	
Surya P. Bhatt, M.D.	University of Alabama at Birmingham	Member	COPD, clinical trials of medications	
Andrea S. Gershon, M.D.	Sunnybrook Research Institute, Canada	Member	COPD outcomes, health services research	
Todd Lee, Pharm.D., Ph.D.	University of Illinois	Member	Pharmacology, COPD medications, polypharmacy	
Huong Q. Nguyen, R.N., Ph.D.	Kaiser Permanente Southern California	Member	COPD, frailty, patient-centered outcomes	
Leah Witt, M.D.	University of San Francisco	Member	Geriatrics, multimorbidity	
Richard Mularski, M.D.	Kaiser Permanente Northwest	Member	COPD and patient-centered outcomes, leadership of clinical trial networks	
Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

Table 2. Key Citations That Informed the Content of the Committee’s First Meeting

Topic	Summary of Key Points	
Burden, impact and complexities of cardiovascular comorbidities in COPD	• Cardiovascular disease is common among individuals with COPD (3–9). For instance, the prevalence of heart failure (7–42%), ischemic cardiovascular disease (2–18%), and arrhythmia (3–21%) is consistently high across cohorts over decades (3–8).

• There is underdiagnosis and underprediction of cardiovascular disease in patients with COPD (66, 67).

• Approximately 35% of deaths among individuals with COPD are attributed to cardiovascular disease (10–12).

• Patients with COPD have markedly increased risk of cardiovascular events in the 30 d after an exacerbation that persists for up to 1 yr (25–28).

• Many patients with COPD with only mild to moderate obstruction by FEV1 are dying of cardiovascular outcomes (13, 68, 69).

• Confirmatory testing for COPD is less common than confirmatory testing for heart failure in patients with both conditions (70–72).

• It is diagnostically difficult to tease apart a COPD exacerbation vs. heart failure exacerbation or cardiac ischemia (36, 38, 73–75).

• Control of cardiovascular risk factors in patients with COPD remains poor (57).

	
Mechanisms and implications of cardiovascular disease in COPD	• Patients with COPD have certain phenotypes that tend to have more or less risk of cardiovascular disease in addition to the historical binary classification of “blue bloater” and “pink puffer” (49, 76, 77).

• Cardiovascular events in patients with COPD increase with number of exacerbations and symptoms of breathlessness but not with FEV1 decline (13, 78–80).

• Incident heart failure in patients with COPD is associated with a 3× increase in mortality at 1 yr (81), but risks of mortality and hospitalization have not been quantified by heart failure severity (i.e., how low the ejection fraction is).

• COPD promotes the occurrence of atrial fibrillation, progression, recurrence after cardioversion, reduced efficacy of catheter-based antiarrhythmic therapy, and worse outcomes (8, 82).

• Smoking, in addition to occupational exposures and lifestyle habits such as diet and exercise, is believed to be the common underlying cause of many of the comorbidities seen in COPD, including cardiovascular disease (18).

• The biological pathways underlying COPD and cardiovascular disease include inflammation (TNF-α, IL-6, CRP, fibrinogen, amyloid, surfactant) and accelerated aging (telomere shortening, cellular senescence, reduced cell proliferation) (19, 20).

• The mechanisms underlying COPD and cardiovascular disease include acute inflammation, oxidative stress, protein imbalance, elastin degradation, hypoxia/hypercapnia, endothelial dysfunction, atherosclerosis, and arterial stiffness (19, 21, 22).

	
Evidence for use of medications in treating coexisting cardiovascular disease in COPD	• COPD treatments affect the cardiovascular system (LABAs, LAMAs, azithromycin) and treatments of cardiovascular disease affect the lung (β-blockers, amiodarone) (19, 29). Some effects may be beneficial, such as the antiinflammatory properties of statins, and others may be detrimental, such as the pulmonary toxicity from amiodarone.

• Pulmonary medications ○ Inhaled β-agonists do not increase cardiovascular events in trials of patients with COPD, but many trials exclude patients with cardiovascular disease. Historically, there has been concern because β-agonists cause tachycardia (61, 83).

○ In meta-regression, inhaled steroid therapy was associated with lower risk of cardiovascular events compared with long-acting bronchodilator therapy, regardless of cardiovascular history (61). However, in randomized clinical trials of patients with COPD, groups receiving inhaled steroid did not have fewer cardiovascular events (SUMMIT comparison groups were ICS, LABA, LAMA, and triple therapy; IMPACT comparison groups were ICS/LABA, LAMA/LABA, and triple therapy) (59, 60). Cardiovascular outcomes were not the primary outcomes of either trial; the primary outcomes were mortality in SUMMIT and annual rate of moderate to severe COPD exacerbations in IMPACT.

○ A 5-d course of azithromycin, which is commonly used in COPD patients to treat exacerbation, was associated with a small absolute increase in the risk of cardiovascular death compared with no antibiotics or amoxicillin, which was most pronounced for patients at highest risk of cardiovascular events (30).

• Cardiac medications ○ Statins do not lower risk of COPD exacerbations or cardiovascular events, though the major trial was done in patients without cardiovascular disease or diabetes (84, 85).

○ Cardioselective (B1) β-blockers alleviate symptoms and improve survival in patients with heart failure but are underused in patients with concurrent COPD because of fear of bronchoconstriction (32–35).

○ β-Blockers should not be used to prevent COPD exacerbations in patients who do not have cardiac indications (55).

○ There were fewer cardiovascular events in patients with COPD with acute myocardial infarction if treated with P2Y12 receptor antagonists vs. thienopyridine (86).

○ Amiodarone causes direct lung toxicity, which can manifest in the form of interstitial pneumonitis, organizing pneumonia, acute respiratory distress syndrome, and diffuse alveolar damage (31).

○ Certain treatments (e.g., SGLT2i) might have a larger benefit in the COPD subgroup with heart failure, though further research is needed to assess if there is truly heterogeneity of treatment effect (54).

	
Patient-centered outcomes for patients with COPD with cardiovascular disease	• Patient-centered outcomes should be incorporated into current clinical trials. The working definition of treatment benefit is a favorable effect on a meaningful aspect of how a patient feels or functions in their usual life. Examples include respiratory symptoms, quality of life, and functional capacity.

• Research activities should engage patients in active, meaningful, collaborative interaction across any and ideally all stages of the research process, where decision making is guided by patients’ contributions as partners, recognizing their specific experiences, values, and expertise (87).

• Physician/hospital payment models and research funding are geared toward managing a patient with one condition as “principal discharge diagnosis,” which is not patient-centric, practical, or reflective of the complexity of their comorbidity profile.

	
Patient perspective	• New technologies (drugs and devices) should be developed to facilitate the care and day-to-day management of COPD. An example is an oxygen support device that automatically titrates to oxygen saturation to promote patient mobility and exercise.

• Care of patients with COPD who have multimorbidity should be streamlined to prevent siloed management among specialists, limit polypharmacy, decrease cost for patients, and improve adherence to guideline-based therapies.

	
Evidence for rehabilitation in patients with COPD with cardiovascular disease	• There are strong published clinical recommendations for the following patients to undertake pulmonary rehabilitation, with choice of telerehabilitation: 1) those with stable COPD and 2) those who have been hospitalized for COPD exacerbation (88, 89).

• Patients with high comorbidity burden, such as those with heart failure, are unlikely to participate in pulmonary rehabilitation (90).

• The goals of pulmonary and cardiac rehabilitation are similar (education, exercise, lifestyle modification, and behavior change), but little is known about combined cardiopulmonary rehabilitation programs among patients with COPD and cardiovascular disease.

	
Health equity in diagnosing and treating patients with COPD and cardiovascular disease	• Disparities exist in both the diagnosis and management of patients with COPD and multimorbidity. Numerous factors are important to consider, such as race, socioeconomic status, sex, and urban/rural residence (91–97).

• Guideline-concordant statin care is less common in patients with both COPD and cardiovascular disease than those with cardiovascular disease alone (98).

• Patients with ischemic heart disease are less likely to receive β-blockers and revascularization if they have COPD (38, 99).

• There is variability in comorbidity profile among patients with COPD of different races (96). For example, hypertension and history of stroke are more common in non-Hispanic Black patients, whereas dyslipidemia and history of myocardial infarction are more common in non-Hispanic White patients.

• There are differences by gender in the prevalence of cardiovascular comorbidities in patients with COPD (97). Women with COPD tended to have more heart failure and hypertension and less ischemic heart disease compared with men with COPD.

	
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; IMPACT = Informing the Pathway of COPD Treatment; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SGLT2i = sodium-glucose cotransporter-2 inhibitors; SUMMIT = Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease.

One important and controversial point of discussion from Day 1 was the concept of COPD as a potential “risk-enhancing factor” for atherosclerotic cardiovascular disease. In the cardiovascular prevention guidelines (44, 45), certain clinical conditions characterized by systemic inflammation, such as rheumatoid arthritis, have been identified as risk-enhancing factors. When a risk-enhancing factor is identified, more intensive primary prevention goals are indicated, because patients’ risk of developing cardiovascular disease is significantly higher. COPD is well known to cause systemic inflammation and increase the risk of cardiovascular disease (46) but is not currently listed as a risk-enhancing factor for primary prevention (45). Experts on the committee believed that research on how to translate existing knowledge about the risk of developing cardiovascular disease in COPD into clinical practice is warranted. They believed that it was a potential missed opportunity not to intensively manage cardiovascular disease risk, which likely explains why so many patients with COPD die of cardiovascular disease.

The 10 domains of gaps identified on Day 1 were mapped along the translational science spectrum from basic and preclinical research to clinical and population science research to knowledge translation and implementation science research (Figure 1). These included 1) mechanisms of disease; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac/pulmonary rehabilitation; and 10) health equity. A word cloud that reflects the frequency of the words said during the meeting on Day 1 by the size of the font can be seen in Figure 2. The locations of the words in the word cloud reflect how they were used in relation to other words.

Figure 1. Span of domains across the translational science spectrum. We used the NHLBI’s translational science spectrum as a framework to generate the list of 10 domains between Days 1 and 2. The domains range from basic science about the mechanisms of disease to the implementation of evidence-based treatments into everyday practice.

Figure 2. Word cloud from transcript of Day 1 committee meeting. This word cloud was generated by feeding the transcript from Day 1 of the committee meeting into an online large language model that examined the frequency of words and their proximity to one another and generated this figure in the shape of the lungs. The words that are larger in size were said more frequently during the committee meeting on Day 1.

On Day 2, the committee unanimously agreed to reposition the two disparity-related topics from the list as ones that cross-cut all other topics. The two specific topics were:1) reduce disparities in the diagnosis and management of patients with COPD and cardiovascular disease (age, gender, race/ethnicity, low literacy, payer), including appropriate and timely diagnosis and adherence to guideline-based recommendations, and 2) expand trial recruitment to include, and potentially focus directly on, patients with COPD and cardiovascular disease, especially those with low socioeconomic status.

After removing the 2 disparity-related topics, the remaining 17 topics underwent Delphi rounds for prioritization. We achieved >80% to fulfill quorum for all rounds of voting, with no one abstaining from voting. Of the 17 topics that were voted on, agreement of ≥70% was achieved for 10 topics in the first round of voting and 2 additional topics in the second round of voting. Figure 3 shows the distribution of responses for each topic during the final round of voting. Table 3 contains a full description of the prioritized list of topics, ordered from high to low summative Likert score from the final round of voting. The range of summative Likert score was −15 to 25. The topic that was overwhelmingly voted to be the top priority was “Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements.” Examples are listed in Table 3 to highlight the types of trials that the committee believed would be most useful.

Figure 3. Breakdown of responses for prioritization of the research topics in final Delphi round across the five-point Likert scale. If a color/percentage is missing along a row, that means that the value was zero, such as strongly disagree for priority 1. The text of each of the 17 prioritized topics is listed in Table 3. Briefly, they are 1) pragmatic trials with patient-centered outcomes, 2) cost-effectiveness of cardiac and respiratory tests, 3) phenotyping, 4) cardiac and pulmonary rehabilitation, 5) knowledge translation about COPD as a risk-enhancing diagnosis, 6) epidemiology of subgroups, 7) leverage lung cancer screening computed tomography scans, 8) simplified inhaler regimens that are accessible, 9) mechanisms of disease, 10) clinician awareness about evidence-based risks of cardiovascular treatments on lung function, 11) optimal roles of clinicians that prioritizes patients’ needs, 12) leverage technology, 13) longitudinal studies following stable and exacerbated patients with cardiac rhythm monitors, 14) risks and benefits of conservative medication management versus advanced cardiac testing/catheterization in patients with COPD with troponin leak, 15) impact of using active language to describe COPD exacerbation, 16) environmental triggers, and 17) performing spirometry in hospitalized patients. COPD = chronic obstructive pulmonary disease.

Table 3. Prioritized List of Research Topics to Fill the Most Urgent Gaps in the Field of Chronic Obstructive Pulmonary Disease and Cardiovascular Disease

Priority	Research Topic	Number of Rounds	Degree of Agreement in Final Round	Summative Likert Score in Final Round	
1	Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements.
Specifically:  • Use pragmatic clinical trial designs to expedite the recruitment and retention of patients with COPD and cardiovascular disease, especially those with low health literacy and poor access to medications.

• Ensure that pulmonary-related data (mMRC, CAT, spirometry) are reported in prospective trials focused on cardiovascular drugs, and cardiac-related data (biomarkers, echocardiographic studies) are reported in prospective trials focused on pulmonary drugs.

• Integrate patient-centered outcomes into trials with the pairing of qualitative and quantitative methods to evaluate the impact of medications and interventions on patients’ symptoms.

• Conduct real-world effectiveness trials of medications in the broad COPD population with concurrent cardiovascular disease, especially medications that decrease the burden of taking multiple inhalers and pills per day (i.e., polypuff, polypill).

• Conduct stepped-wedge implementation trials in large health systems, to examine the benefit of newer medications, such as SGLT2i, in patients with COPD who have indications to receive this class of medication (type 2 diabetes, heart failure, chronic kidney disease).

	1	95%	25	
2	Determine the cost-effectiveness and other measures of benefit (NNT) of cardiac diagnostic tests (Cardiac Injury Score on ECG, biomarkers [natriuretic peptides, troponin], and echocardiography) in stable and exacerbated patients with COPD. Determine the cost-effectiveness and other measures of benefit (NNT) of spirometry with diffusion capacity to assess lung function among patients with cardiovascular disease.	1	82%	14	
3	Refine our knowledge of phenotypes within the COPD population with the goal of understanding patients’ individualized risk of different cardiovascular diseases (i.e., which phenotype predisposes to heart failure, atherosclerotic cardiovascular disease, and atrial fibrillation). Determine the appropriate screening studies and treatments for the different phenotypes.	2	87%	13	
4	Identify and further develop the key elements of pulmonary and cardiac rehabilitation programs that specifically help patients with both COPD and cardiovascular disease, potentially aiming for an integrated cardiopulmonary program.	2	83%	12	
5	Improve knowledge translation by increasing clinicians’ adherence to guidelines on the primary and secondary prevention of cardiovascular disease in patients with COPD and raise awareness of COPD as a “risk-enhancing diagnosis,” which requires more stringent lipid and blood pressure management.	2	82%	9	
6	Define the incidence, prevalence, characteristics, and prognosis of major cardiovascular diseases in patients with COPD using contemporary definitions, including heart failure subtypes (preserved and reduced ejection fraction), acute coronary syndrome subtypes (type 1 and 2 events) and various arrhythmias (both atrial and ventricular).	2	83%	8	
7	Determine the best approach to leverage cardiovascular disease seen on lung cancer screening CT scans (coronary calcium, enlarged aorta, pulmonary artery, atherosclerosis, etc.).	2	71%	7	
8	Develop and test simplified medication and inhaler regimens that are low cost and accessible to those with low literacy who have COPD and cardiovascular disease. Examine the impact of different pricing strategies of medications on patients’ behavior to be adherent with the goal of changing health policy to improve patients’ access.	2	77%	6	
9	Elucidate the mechanisms underlying the relationships between COPD and cardiovascular disease, such as congestive heart failure, atherosclerotic cardiovascular disease, and atrial fibrillation, which are common and affect patients’ long-term trajectory, with the goal of finding targeted therapies that prevent or slow both diseases.	2	77%	5	
10	Raise awareness among clinicians about the evidence-based risks of cardiovascular treatments on lung function (such as statins, β-blockers) and pulmonary treatments on cardiovascular function (such as inhaled steroids, β-agonists).	1	59%	0	
11	Define the optimal roles of primary care physicians, hospitalists, pulmonologists, and cardiologists in treating patients with COPD and cardiovascular disease in both the outpatient and inpatient settings with the goal of prioritizing patients’ needs.	1	65%	−1	
12	Leverage technology to improve various aspects of care for patients with COPD and cardiovascular disease, such as delivery of supplemental oxygen that is automatically titrated to oxygen saturation with movement and participation in telerehabilitation programs.	1	71%	−2	
13	Conduct longitudinal studies following stable and exacerbated patients with cardiac rhythm monitors to examine the risk of undetected or recurrent AF and response to therapy (pharmacologic and ablation).	1	36%	−9	
14	Determine the risks and benefits of conservative medical management versus advanced cardiac testing or catheterization in patients hospitalized with COPD who have elevated troponin.	1	53%	−11	
15	Determine the impact of using active language to describe COPD exacerbation (e.g., “lung attack), given the significantly elevated cardiopulmonary risk over time and specifically in the postexacerbation period.	1	35%	−13	
16	Examine how environmental triggers, such as air pollution, mediate the relationship between COPD and cardiovascular disease.	1	24%	−14	
17	Evaluate the impact of performing spirometry in hospitalized patients with cardiopulmonary symptoms to differentiate between airflow obstruction and other common conditions that cause dyspnea, such as congestive heart failure.	1	24%	−15	
Definition of abbreviations: AF = atrial fibrillation; CAT = COPD assessment test; COPD = chronic obstructive pulmonary disease; CT = computed tomography; ECG = electrocardiography; mMRC = Modified Medical Research Council Dyspnea Scale; NNT = number needed to treat; SGLT2i = sodium-glucose cotransporter-2 inhibitors.

Seventeen participants voted on all questions. Participants were allowed to vote strongly agree or agree on only 5 of 17 priorities to facilitate generating a prioritized list with a gradient. The degree of agreement is the percentage of respondents who voted strongly disagree/disagree or neutral/agree/strongly agree about whether the gap should be considered a top priority, which was defined as significant potential for advancing the field and ultimately improving the lives of patients with COPD and cardiovascular disease. The last column is the summative Likert score, from which the final round was calculated, where strongly disagree was assigned −2, disagree was assigned −1, neutral was assigned 0, agree was assigned +1, and strongly agree was assigned +2. The final list of priorities was then ordered by the final-round summative Likert score.

Discussion

Our expert committee identified and prioritized research topics regarding the diagnosis and management of patients with COPD and cardiovascular disease, specifically heart failure, atherosclerotic cardiovascular disease, and atrial fibrillation. Spanning the full translational science spectrum, the gaps encompassed the following 10 domains: 1) mechanisms of disease; 2) epidemiology; 3) subphenotyping; 4) diagnosis and management; 5) clinical trials; 6) care delivery; 7) medication access, adherence, and side effects; 8) risk factor mitigation; 9) cardiac and pulmonary rehabilitation; and 10) health equity. The committee believed strongly that consideration of disparities should be part of research done across all topics. For the remaining 17 topics, we used robust methods (a modified Delphi consensus-building approach) and successfully achieved quorum for all and agreement for the majority (12 of 17 topics after two rounds of Delphi).

The topic with the highest priority score was “Conduct pragmatic clinical trials with patient-centered outcomes that collect both pulmonary and cardiac data elements.” A pragmatic trial is a clinical trial that tests an intervention in a real-world setting (47). Although multimorbidity is common in COPD (5, 48, 49), patients with comorbid cardiovascular diseases are often excluded from trials in the COPD population (50–52), which hinders our ability to provide evidence-based care to patients in the community. Several examples do exist, though, in which both COPD and cardiovascular disease were addressed: 1) One trial comparing inhaler regimens in patients with COPD specifically enrolled patients with and those without stable cardiac disease, which the investigators defined as no myocardial ischemic event in 6 months, no hospitalization for advanced heart failure, and no life-threatening arrhythmia in 12 months (53). 2) An important lesson was gleaned from a post hoc subgroup analysis of a trial that enrolled patients with COPD with cardiovascular disease; the results suggested that among patients with heart failure, those with COPD had similar relative risk reduction with sodium-glucose cotransporter-2 inhibitors compared with those without COPD, but the absolute risk reduction was greater in those with COPD, likely because of the higher frequency of cardiovascular events in this population (54). 3) A trial randomized patients with moderate to severe COPD who did not already have indications for β-blockers to receive metoprolol and showed no difference in time until exacerbation (55).

Future trials should specifically target the enrollment of patients with COPD with cardiovascular disease and collect both pulmonary and cardiovascular-specific data elements, especially on outcomes that are important to patients, such as symptom relief, ability to do activities of daily living, and exacerbation frequency and acuity. In practice, this means that COPD trials should not exclude patients with cardiovascular disease, and cardiovascular disease trials should characterize the respiratory characteristics of patients better. The optimal trial design should be used, whether that is randomization at the individual level or stepped wedge by provider or clinic. The committee believed strongly that the evidence gained in clinical trials should be practical and useful in community settings, that is, apply to the broad population, be developed in conjunction with community organizations, and reflect the real-world effectiveness of the medications. Ideally, trials that address the real-world effectiveness of medications in patients with COPD and cardiovascular disease, especially those that limit the burden of taking multiple pills or inhalers per day (polypill or polypuff), should be prioritized. Pairing qualitative analysis with quantitative analysis to understand patient perspectives is critical, as well as a focus on vulnerable patient populations. Patients with low literacy and English as a second language should be able to access the medications being tested, so designing the trials to successfully engage with diverse populations is crucial. Given that smoking underlies much of the risk of developing COPD and cardiovascular disease, interventions related to smoking cessation are an important target, as well as research that seeks to understand the differential uptake of smoking cessation tools (56). In addition, trials are needed that examine the benefit of newer medications, such as sodium-glucose cotransporter-2 inhibitors, which could have pleiotropic effects on other organs and, therefore, provide benefit in patients with COPD and multimorbidity who have approved indications for the drugs (type 2 diabetes, heart failure, chronic kidney disease).

After some deliberation, the committee believed that the concept of COPD as a risk-enhancing factor was important. Because patients with COPD are so much more likely than the general population to develop atherosclerotic cardiovascular disease (7), the consensus was that screening and aggressive mitigation of atherosclerotic cardiovascular risk factors in the long term (cholesterol, blood pressure, etc.) might improve outcomes. However, a definitive study has not demonstrated this. Given that this research statement is not intended to make clinical recommendations, the committee believed strongly that the statement should at least call for research to quantify the benefit of treating individuals with COPD and concomitant cardiovascular disease with aggressive risk factor control. Trials that examine cardiac risk screening and aggressive risk factor management strategy would likely strengthen the evidence in favor of treating COPD as a risk-enhancing factor and inform future iterations of clinical guidelines. Patients with COPD and cardiovascular disease should not be excluded from receiving guideline-directed primary and secondary prevention for cardiovascular disease (38, 57).

A recent article in the Journal proposes a shift in the guideline-based paradigm of how to choose which inhalers to initiate first in stable patients with COPD (58). Instead of the 2023 Global Initiative for Chronic Obstructive Lung Disease paradigm of A-B-E classification by Modified Medical Research Council Dyspnea Scale score, COPD Assessment Test score, and number of exacerbations, the authors suggest adding a third dimension (E+ and B+), whereby patients with COPD and known cardiovascular disease should be initiated on triple therapy first. This is based on some evidence, albeit not completely consistent (59), that patients with COPD and cardiovascular disease have better outcomes on inhaled corticosteroid-containing therapy (60, 61). Expert clinical consensus is needed to adjudicate whether the body of evidence exists to support this proposed paradigm.

There are policy implications affecting patients with COPD and cardiovascular disease. For instance, the Centers for Medicare and Medicaid Services has a Hospital Readmission Reduction Program that financially penalizes hospitals for excess readmissions after index admissions for diseases including COPD, acute myocardial infarction, and heart failure (62). Since the penalties were implemented, evidence has shown potential inverse relationships between reduced readmissions and mortality for both COPD and heart failure (63, 64). Understanding the interplay between these two diseases and, ultimately, how hospitalizations related to COPD and heart failure can be prevented is important for reimbursement for hospitals (65).

There are several benefits to the modified Delphi approach we took, but there are also limitations. The virtual Delphi approach allows a large number of experts from distant places to participate. Because we made sure that voting results were anonymous, the group could not be swayed by the votes of individuals. However, the ideas presented in this research statement are based on expert opinion. Also, the committee believed that all of the topics identified are important and worthy of further investigation. Because the goal was to prioritize the topics on the basis of urgency and potential impact, we limited to five the number of votes experts could cast for agreeing or strongly agreeing with a topic being a priority to create a gradient for prioritization. We tried to engage as many stakeholders as possible but did not engage payers (insurance agencies) or pharmaceutical representatives.

Conclusions

This research statement sets forth a prioritized research agenda with the purpose of stimulating high-impact research and improving the lives of patients with COPD and cardiovascular disease. Although topics with lower priority ratings were still deemed to be important by the committee, pragmatic clinical trials with patient-centered outcomes that address health disparities were deemed to be the most urgent.

Acknowledgment

The authors thank Rachel Kaye from the ATS for facilitating the Zoom meetings, specifically the voting during the Delphi rounds. The authors also acknowledge the Behavioral Science and Health Services Research and Clinical Problems assemblies of the ATS for the opportunity to convene this committee.

This official research statement was prepared by an ad hoc subcommittee of the ATS Assembly on Behavioral Science and Health Services Research.

Members of the subcommittee are as follows:

Laura C. Myers, M.D., M.P.H. (Co-Chair)1

Miguel Divo, M.D. (Co-Chair)2

Valerie G. Press, M.D., M.P.H. (Co-Chair)3

R. Graham Barr, M.D., Dr.P.H.4,5*

Surya P. Bhatt, M.D., M.S.P.H.6‡

Mark Dransfield, M.D.6*

Caroline Gainer7§

Andrea S. Gershon, M.D.8*

Alan Hamilton, Ph.D.7§

Nathaniel M. Hawkins, M.D.9‡§

Sadiya S. Khan, M.D., M.Sc.10*‡

Todd Lee, Pharm.D., Ph.D.11ǁ

Peter Lindenauer, M.D.12§

David M. Mannino, M.D.7*

Richard Mularski, M.D.13ǁ

Huong Nguyen, R.N., Ph.D.14ǁ

Nirupama Putcha, M.D., M.H.S.15§

Jennifer K. Quint, M.D.16‡§

Sagar P. Shah, M.D., M.P.H.1‡

Allan Walkey, M.D.17ǁ

J. Michael Wells, M.D., M.S.P.H.6*

Leah J. Witt, M.D.18,19‡

*Discussant.

‡Writer.

§Speaker.

ǁParticipant.

1Kaiser Permanente Northern California, Oakland, California; 2Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; 3University of Chicago, Chicago, Illinois; 4Department of Medicine and 5Department of Epidemiology, Columbia University Medical Center, New York, New York; 6University of Alabama at Birmingham, Birmingham, Alabama; 7COPD Foundation, Miami, Florida; 8University of Toronto, Toronto, Ontario, Canada; 9Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; 10Department of Medicine and Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; 11Department of Medicine, University of Illinois, Chicago, Illinois; 12Baystate Health, Springfield, Massachusetts; 13Kaiser Permanente Northwest, Portland, Oregon; 14Kaiser Permanente Southern California, Pasadena, California; 15Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medicine, Baltimore, Maryland; 16School of Public Health, Imperial College London, London, United Kingdom; 17University of Massachusetts, Worcester, Massachusetts; and 18Division of Pulmonary, Critical Care, Allergy and Sleep Medicine and 19Division of Geriatrics, Department of Medicine, University of California, San Francisco, San Francisco, California

This official research statement of the American Thoracic Society was approved May 2024

Supported by the American Thoracic Society.

A data supplement for this article is available via the Supplements tab at the top of the online article.

Subcommittee Disclosures: L.C.M. holds stock in Amgen. J.K.Q. served as a consultant for AstraZeneca, Chiesi, GlaxoSmithKline, and Insmed; and received research support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Health Data Research, Insmed, the Medical Research Council, NIHR, and Sanofi. N.M.H. served as a consultant, speaker, and received research support from AstraZeneca. N.P. served on an advisory board and as a consultant for GlaxoSmithKline and Verona; and received research support from NIH/NIEHS. A.H. served as a consultant for the COPD Foundation. P.L. served as a consultant for Kivo Health. J.M.W. served on an advisory board for GlaxoSmithKline and Takeda; served on an endpoint review committee for AstraZeneca and Bavarian Nordic; holds patent PCT/GB2021/050658 with Mereo BioPharma; received research support from Alpha-1 Foundation, ARCUS-Med, Department of Veteran Affairs, GlaxoSmithKline, Grifols, InhibrX, Medscape, Mereo BioPharma, NIH/NHLBI, Takeda, and Verona Pharma; and holds stock in Alveolus Bio. L.J.W. received honoraria from Curbsiders Podcast, Elsevier, and Medscape/WebMD; received research support from the Health Resources and Services Administration; and received royalties from McGraw Hill. H.N. served on an advisory board for NIH/UCSF; and received research support from NIH and PCORI. A.W. received research support from NIH/NHLBI; and received royalties from UpToDate. D.M.M. served as a consultant for AstraZeneca, Genentech, GlaxoSmithKline, Regeneron, and UpToDate; served as an expert witness for Schlesinger Law Firm; served in a leadership role for the COPD Foundation; received royalties from UpToDate; and holds stock in GlaxoSmithKline. S.P.B. served on an advisory board for GlaxoSmithKline, NIH, and Regeneron; served as a consultant for Apreo, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Regeneron, Sanofi, and Verona; received honoraria from Horizon CME, Integrity CE, and Medscape; received research support from Genentech, NIH, Nuvaira, and Sanofi/Regeneron; and received royalties from Springer. R.G.B. served in a leadership role for the COPD foundation; and received research support from the American Lung Association, the COPD Foundation, and the NIH. R.M. served on an advisory board for the COPD Foundation; and received research support from PCORI, Pfizer, and Sanofi. M.D. served on the board of directors for the COPD Foundation; served as a consultant for Aer Therapeutics, Apreo, AstraZeneca, the COPD Foundation, Genentech, GlaxoSmithKline, Novartis, Pulmonx, and Teva; received research support from the American Lung Association, the NIH, and the U.S. Department of Defense; received royalties from UpToDate; and received travel support from GlaxoSmithKline. S.S.K. received research support from the NHLBI. A.S.G. served on an advisory committee for the Canadian Thoracic Society, the Chest Foundation, and the European Respiratory Society; served as a mentor for Novartis; and received research support from the Canadian Institute of Health Research and the Ontario Ministry of Economic Development and Innovation. M.D. served as a consultant for Regeneron and Sanofi. V.G.P. served as a consultant for Humana and Vizient; served on the data safety and monitoring board for NIH and PCORI; received honoraria from AboutHealth COPD Collaborative, Dell, KUMC, and UCLA; served in a leadership role for the Chest Foundation, Journal of COPD Foundation, and Journal of General Internal Medicine; received research support from the NIH/NHLBI and the Agency for Health Care Research and Quality; and received travel support from the American College of Physicians and the Society of Hospital Medicine. S.P.S., T.L., and C.G. reported no commercial or relevant non-commercial interests from ineligible companies.
==== Refs
References

1. Boers E Barrett M Su JG Benjafield AV Sinha S Kaye L et al. Global burden of chronic obstructive pulmonary disease through 2050 JAMA Netw Open 2023 6 e2346598 38060225
2. Vaduganathan M Mensah George A Turco Justine V Fuster V Roth Gregory A The global burden of cardiovascular diseases and risk J Am Coll Cardiol 2022 80 2361 2371 36368511
3. Divo M Cote C de Torres JP Casanova C Marin JM Pinto-Plata V et al. BODE Collaborative Group Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med 2012 186 155 161 22561964
4. Balbirsingh V Mohammed AS Turner AM Newnham M Cardiovascular disease in chronic obstructive pulmonary disease: a narrative review Thorax 2022 10.1136/thoraxjnl-2021-218333
5. Fabbri LM Celli BR Agustí A Criner GJ Dransfield MT Divo M et al. COPD and multimorbidity: recognising and addressing a syndemic occurrence Lancet Respir Med 2023 11 1020 1034 37696283
6. Zhu Z Wang X Li X Lin Y Shen S Liu C-L et al. International COPD Genetics Consortium Genetic overlap of chronic obstructive pulmonary disease and cardiovascular disease-related traits: a large-scale genome-wide cross-trait analysis Respir Res 2019 20 64 30940143
7. Chen W Thomas J Sadatsafavi M FitzGerald JM Risk of cardiovascular comorbidity in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis Lancet Respir Med 2015 3 631 639 26208998
8. Ioannides AE Tayal U Quint JK Spirometry in atrial fibrillation: what’s the catch? Expert Rev Respir Med 2023 17 937 950 37937396
9. Morgan AD Rothnie KJ Bhaskaran K Smeeth L Quint JK Chronic obstructive pulmonary disease and the risk of 12 cardiovascular diseases: a population-based study using UK primary care data Thorax 2018 73 877 879 29438071
10. Vilkman S Keistinen T Tuuponen T Kivela SL Survival and cause of death among elderly chronic obstructive pulmonary disease patients after first admission to hospital Respiration 1997 64 281 284 9257363
11. McGarvey LP John M Anderson JA Zvarich M Wise RA TORCH Clinical Endpoint Committee Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee Thorax 2007 62 411 415 17311843
12. Brassington K Selemidis S Bozinovski S Vlahos R New frontiers in the treatment of comorbid cardiovascular disease in chronic obstructive pulmonary disease Clin Sci (Lond) 2019 133 885 904 30979844
13. Whittaker H Rothnie KJ Quint JK Cause-specific mortality in COPD subpopulations: a cohort study of 339 647 people in England Thorax 2024 79 202 208 37328279
14. Wilson KC Gould MK Krishnan JA Boyd CM Brozek JL Cooke CR et al. ATS Guideline Methodology Working Group An official American Thoracic Society workshop report: a framework for addressing multimorbidity in clinical practice guidelines for pulmonary disease, critical illness, and sleep disorders Ann Am Thorac Soc 2016 13 S12 S21 26963362
15. Roversi S Fabbri LM Sin DD Hawkins NM Agusti A Chronic obstructive pulmonary disease and cardiac diseases: an urgent need for integrated care Am J Respir Crit Care Med 2016 194 1319 1336 27589227
16. Ghoorah K De Soyza A Kunadian V Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review Cardiol Rev 2013 21 196 202 23095685
17. Shnoda M Gajjar K Ivanova V COPD and cardiovascular disease: a review of association, interrelationship, and basic principles for integrated management Crit Care Nurs Q 2021 44 91 102 33234862
18. Barnes PJ Celli BR Systemic manifestations and comorbidities of COPD Eur Respir J 2009 33 1165 1185 19407051
19. Morgan AD Zakeri R Quint JK Defining the relationship between COPD and CVD: what are the implications for clinical practice? Ther Adv Respir Dis 2018 12 1753465817750524 29355081
20. Maclay JD MacNee W Cardiovascular disease in COPD: mechanisms Chest 2013 143 798 807 23460157
21. Trinkmann F Saur J Borggrefe M Akin I Cardiovascular comorbidities in chronic obstructive pulmonary disease (COPD)—current considerations for clinical practice J Clin Med 2019 8 69 30634565
22. Romiti GF Corica B Pipitone E Vitolo M Raparelli V Basili S et al. AF-COMET International Collaborative Group Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients Eur Heart J 2021 42 3541 3554 34333599
23. Barr RG Bluemke DA Ahmed FS Carr JJ Enright PL Hoffman EA et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling N Engl J Med 2010 362 217 227 20089972
24. Lammi MR Ciccolella D Marchetti N Kohler M Criner GJ Increased oxygen pulse after lung volume reduction surgery is associated with reduced dynamic hyperinflation Eur Respir J 2012 40 837 843 22267766
25. Dransfield MT Criner GJ Halpin DMG Han MK Hartley B Kalhan R et al. Time-dependent risk of cardiovascular events following an exacerbation in patients with chronic obstructive pulmonary disease: post hoc analysis from the IMPACT trial J Am Heart Assoc 2022 11 e024350 36102236
26. Hawkins NM Nordon C Rhodes K Talukdar M McMullen S Ekwaru P et al. Heightened long-term cardiovascular risks after exacerbation of chronic obstructive pulmonary disease Heart 2024 110 702 709 38182279
27. Rothnie KJ Connell O Müllerová H Smeeth L Pearce N Douglas I et al. Myocardial infarction and ischemic stroke after exacerbations of chronic obstructive pulmonary disease Ann Am Thorac Soc 2018 15 935 946 29723057
28. Graul EL Nordon C Rhodes K Marshall J Menon S Kallis C et al. Temporal risk of non-fatal cardiovascular events post COPD exacerbation: a population-based study Am J Respir Crit Care Med 2024 209 960 972 38127850
29. Rabe KF Hurst JR Suissa S Cardiovascular disease and COPD: dangerous liaisons? Eur Respir Rev 2018 27 180057 30282634
30. Ray WA Murray KT Hall K Arbogast PG Stein CM Azithromycin and the risk of cardiovascular death N Engl J Med 2012 366 1881 1890 22591294
31. Papiris SA Triantafillidou C Kolilekas L Markoulaki D Manali ED Amiodarone: review of pulmonary effects and toxicity Drug Saf 2010 33 539 558 20553056
32. Hawkins NM Petrie MC Macdonald MR Jhund PS Fabbri LM Wikstrand J et al. Heart failure and chronic obstructive pulmonary disease the quandary of beta-blockers and beta-agonists J Am Coll Cardiol 2011 57 2127 2138 21596228
33. Salpeter S Ormiston T Salpeter E Cardioselective beta-blockers for chronic obstructive pulmonary disease Cochrane Database Syst Rev 2005 2005 CD003566 16235327
34. Hawkins NM MacDonald MR Petrie MC Chalmers GW Carter R Dunn FG et al. Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial Eur J Heart Fail 2009 11 684 690 19460848
35. Agusti A Böhm M Celli B Criner GJ Garcia-Alvarez A Martinez F et al. GOLD COPD document 2023: a brief update for practicing cardiologists Clin Res Cardiol 2023 113 195 204 37233751
36. Axson EL Bottle A Cowie MR Quint JK Relationship between heart failure and the risk of acute exacerbation of COPD Thorax 2021 76 807 814 33927022
37. Celli BR Fabbri LM Aaron SD Agusti A Brook RD Criner GJ et al. Differential diagnosis of suspected chronic obstructive pulmonary disease exacerbations in the acute care setting: best practice Am J Respir Crit Care Med 2023 207 1134 1144 36701677
38. Rothnie KJ Smeeth L Herrett E Pearce N Hemingway H Wedzicha J et al. Closing the mortality gap after a myocardial infarction in people with and without chronic obstructive pulmonary disease Heart 2015 101 1103 1110 25765553
39. Rana JS Khan SS Lloyd-Jones DM Sidney S Changes in mortality in top 10 causes of death from 2011 to 2018 J Gen Intern Med 2021 36 2517 2518 32705476
40. Bhatt SP Wells JM Dransfield MT Cardiovascular disease in COPD: a call for action Lancet Respir Med 2014 2 783 785 25298057
41. National Heart, Lung, and Blood Institute Bethesda, MD National Heart, Lung, and Blood Institute 2023 https://www.nhlbi.nih.gov/science/research-spectrum
42. Nair R Aggarwal R Khanna D Methods of formal consensus in classification/diagnostic criteria and guideline development Semin Arthritis Rheum 2011 41 95 105 21420149
43. Williamson K The Delphi method Williamson K Research methods for students, academics and professionals New York Elsevier Science and Technology 2002 209 220
44. Arnett DK Goodman RA Halperin JL Anderson JL Parekh AK Zoghbi WA AHA/ACC/HHS strategies to enhance application of clinical practice guidelines in patients with cardiovascular disease and comorbid conditions: from the American Heart Association, American College of Cardiology, and US Department of Health and Human Services Circulation 2014 130 1662 1667 25212466
45. Arnett DK Blumenthal RS Albert MA Buroker AB Goldberger ZD Hahn EJ et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Circulation 2019 140 e596 e646 30879355
46. Walter RE Wilk JB Larson MG Vasan RS Keaney JF Lipinska I et al. Systemic inflammation and COPD: the Framingham Heart Study Chest 2008 133 19 25 17908709
47. Ford I Norrie J Pragmatic trials N Engl J Med 2016 375 454 463 27518663
48. Divo M Celli BR Multimorbidity in patients with chronic obstructive pulmonary disease Clin Chest Med 2020 41 405 419 32800195
49. Divo MJ Casanova C Marin JM Pinto-Plata VM de-Torres JP Zulueta JJ et al. BODE Collaborative Group COPD comorbidities network Eur Respir J 2015 46 640 650 26160874
50. Papi A Vestbo J Fabbri L Corradi M Prunier H Cohuet G et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial Lancet 2018 391 1076 1084 29429593
51. Singh D Papi A Corradi M Pavlišová I Montagna I Francisco C et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting beta2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial Lancet 2016 388 963 973 27598678
52. Vogelmeier C Hederer B Glaab T Schmidt H Rutten-van Mölken MPMH Beeh KM et al. POET-COPD Investigators Tiotropium versus salmeterol for the prevention of exacerbations of COPD N Engl J Med 2011 364 1093 1103 21428765
53. Wise RA Anzueto A Cotton D Dahl R Devins T Disse B et al. TIOSPIR Investigators Tiotropium Respimat inhaler and the risk of death in COPD N Engl J Med 2013 369 1491 1501 23992515
54. Dewan P Docherty KF Bengtsson O de Boer RA Desai AS Drozdz J et al. Effects of dapagliflozin in heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: an analysis of DAPA-HF Eur J Heart Fail 2021 23 632 643 33368858
55. Dransfield MT Voelker H Bhatt SP Brenner K Casaburi R Come CE et al. BLOCK COPD Trial Group Metoprolol for the prevention of acute exacerbations of COPD N Engl J Med 2019 381 2304 2314 31633896
56. Smith CE Hill SE Amos A Impact of population tobacco control interventions on socioeconomic inequalities in smoking: a systematic review and appraisal of future research directions Tob Control 2020 30 e87 e95 32994297
57. Hawkins NM Peterson S Ezzat AM Vijh R Virani SA Gibb A et al. Control of cardiovascular risk factors in patients with chronic obstructive pulmonary disease Ann Am Thorac Soc 2022 19 1102 1111 35007497
58. Kostikas K Gogali A Hillas G Cardiovascular disease and COPD: adding a third dimension to the ABE GOLD 2023 COPD classification Am J Respir Crit Care Med 2023 208 502 504 37311251
59. Vestbo J Anderson JA Brook RD Calverley PMA Celli BR Crim C et al. SUMMIT Investigators Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial Lancet 2016 387 1817 1826 27203508
60. Lipson DA Barnhart F Brealey N Brooks J Criner GJ Day NC et al. IMPACT Investigators Once-daily single-inhaler triple versus dual therapy in patients with COPD N Engl J Med 2018 378 1671 1680 29668352
61. Gadhvi K Kandeil M Raveendran D Choi J Davies N Nanchahal S et al. Inhaled corticosteroids and risk of cardiovascular disease in chronic obstructive pulmonary disease: a systematic review and meta-regression Chronic Obstr Pulm Dis 2023 10 317 327 37289196
62. Centers for Medicare and Medicaid Services Hospital Readmissions Reduction Program Baltimore, MD Centers for Medicare and Medicaid Services 2019 https://www.cms.gov/medicare/medicare-fee-for-service-payment/acuteinpatientpps/readmissions-reduction-program.html
63. Puebla Neira DA Hsu ES Kuo YF Ottenbacher KJ Sharma G Readmissions Reduction Program, mortality and readmissions for chronic obstructive pulmonary disease Am J Respir Crit Care Med 2020 203 437 446
64. Wadhera RK Joynt Maddox KE Wasfy JH Haneuse S Shen C Yeh RW Association of the Hospital Readmissions Reduction Program with mortality among Medicare beneficiaries hospitalized for heart failure, acute myocardial infarction, and pneumonia JAMA 2018 320 2542 2552 30575880
65. Press VG Myers LC Feemster LC Preventing COPD readmissions under the hospital readmissions reduction program: how far have we come? Chest 2021 159 996 1006 33065106
66. Groenewegen A Zwartkruis VW Rienstra M Hollander M Koffijberg H Cramer MJM et al. Improving early diagnosis of cardiovascular disease in patients with type 2 diabetes and COPD: protocol of the RED-CVD cluster randomised diagnostic trial BMJ Open 2021 11 e046330
67. Amegadzie JE Gao Z Quint JK Russell R Hurst JR Lee TY et al. QRISK3 underestimates the risk of cardiovascular events in patients with COPD Thorax 2024 79 718 724 38050168
68. Lenoir A Whittaker H Gayle A Jarvis D Quint JK Mortality in non-exacerbating COPD: a longitudinal analysis of UK primary care data Thorax 2023 78 904 911 36423926
69. Gayle AV Minelli C Quint JK Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis BMC Pulm Med 2022 22 28 34998380
70. Damarla M Celli BR Mullerova HX Pinto-Plata VM Discrepancy in the use of confirmatory tests in patients hospitalized with the diagnosis of chronic obstructive pulmonary disease or congestive heart failure Respir Care 2006 51 1120 1124 17005056
71. Press VG Cifu AS White SR Screening for chronic obstructive pulmonary disease JAMA 2017 318 1702 1703 29114819
72. Spero K Bayasi G Beaudry L Barber KR Khorfan F Overdiagnosis of COPD in hospitalized patients Int J Chron Obstruct Pulmon Dis 2017 12 2417 2423 28860736
73. Prieto Centurion V Huang F Naureckas ET Camargo CA Charbeneau J Joo MJ et al. Confirmatory spirometry for adults hospitalized with a diagnosis of asthma or chronic obstructive pulmonary disease exacerbation BMC Pulm Med 2012 12 73 23217023
74. Gulea C Zakeri R Kallis C Quint JK Impact of COPD and asthma on in-hospital mortality and management of patients with heart failure in England and Wales: an observational analysis BMJ Open 2022 12 e059122
75. Gulea C Zakeri R Quint JK Differences in outcomes between heart failure phenotypes in patients with coexistent chronic obstructive pulmonary disease: a cohort study Ann Am Thorac Soc 2022 19 971 980 34905461
76. Angelini ED Yang J Balte PP Hoffman EA Manichaikul AW Sun Y et al. Pulmonary emphysema subtypes defined by unsupervised machine learning on CT scans Thorax 2023 78 1067 1079 37268414
77. Martinez CH Mannino DM Divo MJ Defining COPD-related comorbidities, 2004–2014 Chronic Obstr Pulm Dis 2014 1 51 63 28848811
78. Whittaker HR Bloom C Morgan A Jarvis D Kiddle SJ Quint JK Accelerated FEV1 decline and risk of cardiovascular disease and mortality in a primary care population of COPD patients Eur Respir J 2021 57 2000918 32972984
79. Bhatt SP Wells JM Kinney GL Washko GR Budoff M Kim Y-I et al. COPDGene Investigators β-Blockers are associated with a reduction in COPD exacerbations Thorax 2016 71 8 14 26283710
80. Dransfield MT Rowe SM Johnson JE Bailey WC Gerald LB Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD Thorax 2008 63 301 305 17951276
81. Axson EL Sundaram V Bloom CI Bottle A Cowie MR Quint JK Temporal trends in the incidence of heart failure among patients with COPD and its association with mortality Ann Am Thorac Soc 2020 17 939 948 32275836
82. Simons SO Elliott A Sastry M Hendriks JM Arzt M Rienstra M et al. Chronic obstructive pulmonary disease and atrial fibrillation: an interdisciplinary perspective Eur Heart J 2021 42 532 540 33206945
83. Bermingham M O’Callaghan E Dawkins I Miwa S Samsudin S McDonald K et al. Are beta2-agonists responsible for increased mortality in heart failure? Eur J Heart Fail 2011 13 885 891 21791542
84. Criner GJ Connett JE Aaron SD Albert RK Bailey WC Casaburi R et al. Canadian Institutes of Health Research Simvastatin for the prevention of exacerbations in moderate-to-severe COPD N Engl J Med 2014 370 2201 2210 24836125
85. Young RP Hopkins RJ Agusti A Statins as adjunct therapy in COPD: how do we cope after STATCOPE? Thorax 2014 69 891 894 25015240
86. Andell P James SK Cannon CP Cyr DD Himmelmann A Husted S et al. PLATO Investigators Ticagrelor versus clopidogrel in patients with acute coronary syndromes and chronic obstructive pulmonary disease: an analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial J Am Heart Assoc 2015 4 e002490 26452988
87. Harrington RL Hanna ML Oehrlein EM Camp R Wheeler R Cooblall C et al. Defining patient engagement in research: results of a systematic review and analysis. Report of the ISPOR Patient-Centered Special Interest Group Value Health 2020 23 677 688 32540224
88. Lindenauer PK Stefan MS Pekow PS Mazor KM Priya A Spitzer KA et al. Association Between initiation of pulmonary rehabilitation after hospitalization for COPD and 1-year survival among Medicare beneficiaries JAMA 2020 323 1813 1823 32396181
89. Rochester CL Alison JA Carlin B Jenkins AR Cox NS Bauldoff G et al. Pulmonary rehabilitation for adults with chronic respiratory disease: an official American Thoracic Society clinical practice guideline Am J Respir Crit Care Med 2023 208 e7 e26 37581410
90. Spitzer KA Stefan MS Priya A Pack QR Pekow PS Lagu T et al. Participation in pulmonary rehabilitation following hospitalization for COPD among Medicare beneficiaries Ann Am Thorac Soc 2019 16 99 106 30417670
91. Ejike CO Woo H Galiatsatos P Paulin LM Krishnan JA Cooper CB et al. Contribution of individual and neighborhood factors to racial disparities in respiratory outcomes Am J Respir Crit Care Med 2021 203 987 997 33007162
92. McCormack MC Balasubramanian A Matsui EC Peng RD Wise RA Keet CA Race, lung function, and long-term mortality in the National Health and Nutrition Examination Survey III Am J Respir Crit Care Med 2022 205 723 724 34597248
93. Gaffney AW Hawks L White AC Woolhandler S Himmelstein D Christiani DC et al. Health care disparities across the urban-rural divide: a national study of individuals with COPD J Rural Health 2022 38 207 216 33040358
94. Zarrabian B Mirsaeidi M A trend analysis of chronic obstructive pulmonary disease mortality in the United States by race and sex Ann Am Thorac Soc 2021 18 1138 1146 33347376
95. Malla G Bodduluri S Sthanam V Sharma G Bhatt SP Access to pulmonary rehabilitation among Medicare beneficiaries with chronic obstructive pulmonary disease Ann Am Thorac Soc 2023 20 516 522 36476450
96. Lee H Shin SH Gu S Zhao D Kang D Joi YR et al. Racial differences in comorbidity profile among patients with chronic obstructive pulmonary disease BMC Med 2018 16 178 30285854
97. Almagro P López García F Cabrera FJ Montero L Morchón D Díez J et al. Grupo Epoc de la Sociedad Española de Medicina Interna Comorbidity and gender-related differences in patients hospitalized for COPD: the ECCO study Respir Med 2010 104 253 259 19879744
98. Krishnan JK Mallya SG Nahid M Baugh AD Han MK Aronson KI et al. Disparities in guideline concordant statin treatment in individuals with chronic obstructive pulmonary disease Chronic Obstr Pulm Dis 2023 10 369 379 37410623
99. Quint JK Herrett E Bhaskaran K Timmis A Hemingway H Wedzicha JA et al. Effect of β blockers on mortality after myocardial infarction in adults with COPD: population based cohort study of UK electronic healthcare records BMJ 2013 347 f6650 24270505
