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.