Management of the patient with COPD and cardiovascular disease

INTRODUCTION — Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD), which includes coronary heart disease, peripheral artery disease, and cerebrovascular disease, share tobacco abuse as a major risk factor. Thus, these two disorders commonly coexist. In addition, CVD is a leading cause of death among patients with COPD.

The management of patients with concurrent COPD and CVD will be reviewed here. The diagnosis and management of COPD and coronary heart disease occurring independently are discussed separately. (See "Chronic obstructive pulmonary disease: Diagnosis and staging" and "Stable COPD: Initial pharmacologic management" and "COPD exacerbations: Management" and "Chronic coronary syndrome: Overview of care" and "Screening for coronary heart disease".)

COPD/CVD RELATIONSHIP — COPD and CVD frequently coexist, and the presence of one can affect outcomes in the other [1]. As symptoms can overlap, differentiating the relative contributions of these diseases to a given patient’s symptoms can be challenging.

Coexistence of COPD and CVD — The frequent coexistence of COPD and CVD has been observed in several studies [2-5]. As an example, a study from a large United Kingdom database of more than 1.2 million patients over age 35 identified almost 30,000 patients with COPD; these patients were nearly five times more likely to have cardiovascular disease than those without COPD [2]. In a separate study of 351 patients with advanced COPD, clinically significant coronary disease was identified by angiography in 60 percent and was occult in 53 percent [3]. In a meta-analysis, patients with COPD were more likely to be diagnosed with cardiovascular disease (OR 2.46; 95% CI 2.02-3.00) than patients without COPD [6]. The cardiovascular diseases included ischemic heart disease, cardiac dysrhythmia, heart failure, diseases of the pulmonary circulation, and diseases of the systemic arteries.

Impact of comorbid disease on outcomes — A large number of observational studies have found that the coexistence of COPD and cardiovascular disease has an important impact on clinical outcomes.

Cardiovascular morbidity and mortality in patients with COPD [7-12]:

●Patients with COPD may have independently increased risk for cardiovascular disease and mortality beyond known cardiovascular disease risk factors.

In a large population-based cohort study of 5.8 million individuals age ≥40 years without known CVD, of whom approximately 150,000 had a diagnosis of COPD, rates of acute MI, stroke, or cardiovascular death over the following eight years were 3.3 times higher in patients with compared with those without COPD [11]. The rate of these major cardiovascular outcomes remained 25 percent higher in COPD patients (HR 1.25, 95% CI 1.23-1.37) even after adjusting for age, sex, smoking, sociodemographic characteristics, comorbidities, health care utilization, and laboratory testing typically used in robust cardiovascular risk models. Other large database studies have suggested that the increased cardiovascular risk is dose-dependent, with an approximately 20 to 30 percent relative increase in cardiovascular events and mortality for each fall in forced expiratory volume in 1 second (FEV₁) by 10 percent predicted [9].

●The cause of increased cardiovascular risk in patients with COPD beyond the traditional risk factors is uncertain. In one study of over 1000 patients with COPD from the National Health and Nutrition Examination, factors associated with risk of cardiovascular disease included male sex, older age, smoking history, being overweight, history of blood transfusions, heart disease in close relatives, and higher leukocyte or monocyte counts [12].

●Risk for cardiovascular events appears to be acutely elevated following COPD exacerbations. Among 5696 patients with COPD, an increased risk of myocardial infarction (incidence rate ratio [IRR] 2.58 [95% CI 2.26-2.95]) and stroke (IRR 1.97 [95% CI 1.66-2.33]) was noted in the days to weeks after an exacerbation of COPD [7].

Effect of COPD on morbidity and mortality in patients with CVD [13-16]:

●Patients with COPD are more likely to have adverse outcomes after interventions for cardiovascular disease. For example, in a study of 3249 patients with an acute ST-elevation myocardial infarction, COPD was a strong independent predictor of the composite end-point of death or cardiogenic shock [13]. Similarly, among 14,346 patients who underwent percutaneous coronary intervention (PCI) at a single center, COPD was a significant independent risk factor for overall mortality, cardiac mortality, and myocardial infarction [14].

●Cardiac explanations for these poorer outcomes are suggested by a separate study of patients undergoing PCI compared subjects with and without COPD (860 and 10,048, respectively) [15]. The patients with COPD had a lower mean ejection fraction and a greater number of significant coronary lesions. As in the studies above, the COPD group also carried a higher mortality rate and a greater rate of repeat revascularization.

●The impact of COPD on vascular stiffness has also been examined. In a prospective study of 98 patients with stable COPD, 55 of whom experienced a subsequent exacerbation, increased arterial stiffness was associated with more frequent exacerbations, and arterial stiffness rose further during acute exacerbations [17]. The degree of arterial stiffness was also related to several inflammatory biomarkers in COPD.

COPD is also a risk factor for supraventricular and ventricular arrhythmias. The risk factors for and management of arrhythmias in patients with COPD are discussed separately. (See "Arrhythmias in COPD".)

EVALUATION AND DIAGNOSIS OF CHD IN PATIENTS WITH COPD — The symptoms of dyspnea and chest tightness are common to COPD and coronary heart disease (CHD). In patients with known COPD, uncontrolled dyspnea and/or chest tightness could be due to refractory COPD or concomitant CHD. Due to the frequent co-existence of these diseases and the potential diagnostic uncertainty of the symptoms, physicians caring for patients with COPD need to have a low threshold for performing additional diagnostic testing to identify CHD.

Myocardial ischemia — Since exacerbations of both COPD and CHD are often signaled by dyspnea, patients and clinicians may find it challenging to know which disease requires urgent treatment. Classic symptoms of a COPD flare (eg, dyspnea, cough, wheezing, and change in sputum) may point correctly to the lung, while new electrocardiographic signs of ischemia may prove that the heart is the culprit. Alternatively, both organ systems may be involved and difficult to distinguish. (See "Approach to the adult with dyspnea in the emergency department" and "Troponin testing: Clinical use".)

For ambulatory patients with COPD and symptoms that could be attributable to myocardial ischemia, we typically perform a baseline electrocardiogram and dobutamine stress imaging, as exercise limitations may preclude exercise stress testing, and potential bronchoconstriction is often a contraindication to vasodilator radionuclide myocardial perfusion imaging. (See "Approach to the patient with dyspnea" and "Approach to the patient with suspected angina pectoris".)

For patients presenting to the hospital with dyspnea and chest tightness, an elevated serum cardiac troponin frequently, but not always, indicates the presence of coronary artery disease. Among 242 patients admitted for an exacerbation of COPD, 24 had a raised troponin and 20 had chest pain and/or serial electrocardiogram (ECG) changes [18]. However, neither chest pain nor serial ECG changes were statistically associated with elevated troponin, suggesting that a raised troponin in the context of a COPD exacerbation is not necessarily indicative of myocardial injury. In a separate study, highly sensitive cardiac troponin (hs-cTnT) was measured in 50 patients admitted with an acute exacerbation of COPD and 124 stable patients in a pulmonary rehabilitation hospital [19]. The ratio of hs-cTnT in those with a COPD exacerbation was significantly higher than those with stable COPD, ratio 5.67 (95% CI 4.0-7.86). However, the specific determinants of hs-cTnT elevation were unclear, as neither hypoxic vasoconstriction nor underlying cardiovascular disease (CVD) were statistically associated with the increase in hs-cTnT. (See "Troponin testing: Clinical use" and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome".)

Heart failure — Unrecognized heart failure can be a problem in the diagnosis and management of patients with COPD. The frequency of undiagnosed heart failure among ambulatory patients was examined in a cross-sectional study of 244 older adults with COPD [20]. Previously unrecognized heart failure was identified in 21 percent, and ischemic heart disease was judged to be the most common cause of heart failure. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Differential diagnosis'.)

Similarly, for patients presenting to the hospital, symptoms of an exacerbation of COPD overlap with acute worsening of heart failure. In a study examining the ability of N-terminal pro-brain natriuretic peptide (NT pro-BNP) and troponin T to differentiate an acute exacerbation of COPD from left heart dysfunction, 46 of the 148 patients (31 percent) were judged to have both a COPD exacerbation and heart failure [21].

Thus, we have a low threshold to obtaining an echocardiogram and brain natriuretic peptide (BNP or N-terminal pro-BNP) in patients with a COPD exacerbation to make sure heart failure is not overlooked. However, caution is needed in the evaluation of BNP/NT-proBNP results in patients with severe COPD, as pulmonary hypertension can lead to an elevated BNP. In some patients a chest radiograph can help identify heart failure, but bullous emphysema can lead to an atypical appearance of heart failure. (See "Natriuretic peptide measurement in heart failure" and "COPD exacerbations: Clinical manifestations and evaluation", section on 'Differential diagnosis'.)

NONPHARMACOLOGIC THERAPIES — A number of nonpharmacologic therapies may help reduce symptoms and improve quality of life in patients with concomitant COPD and CVD. These interventions have been evaluated in patients with either COPD or CVD but have not been examined extensively when both diseases are present.

Smoking cessation — Smoking cessation is essential to improving outcomes in patients with comorbid COPD and CVD. Behavioral and pharmacologic interventions (eg, nicotine replacement therapy, bupropion, varenicline) to help patients with smoking cessation are discussed separately. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation" and "Pharmacotherapy for smoking cessation in adults".)

Nicotine replacement therapy is indicated for ambulatory patients with COPD despite the presence of CVD. The risk of coronary events (eg, cardiac arrest, myocardial infarction, admission to the hospital for CVD events) is lower among users of nicotine replacement than placebo. The issue of whether nicotine replacement can be started during a hospitalization for myocardial infarction has not been well studied, but cautious initiation during the hospitalization or at the time of discharge is thought to be reasonable. The use of nicotine replacement in patients with coronary artery disease (CAD) or acute myocardial infarction is discussed separately. (See "Cardiovascular effects of nicotine", section on 'Safety of nicotine replacement therapy' and "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Smoking cessation'.)

Cardiopulmonary rehabilitation — A number of studies and systematic reviews have demonstrated the benefits of exercise training in patients with either COPD or CVD, but data are more limited regarding the benefit of exercise training in patients with comorbid COPD and CAD [22]. Observational studies have yielded conflicting results regarding the effect of comorbid CAD on the response to pulmonary rehabilitation. These studies are described in greater detail separately. (See "Pulmonary rehabilitation", section on 'Effect of comorbidities'.)

Patients with COPD who have limited exercise capacity can often achieve an increase in their activity level with pulmonary rehabilitation. We typically refer patients to a pulmonary rehabilitation program, unless chest pain or myocardial ischemia is noted on an exercise pretest. These patients are referred for cardiac evaluation and possibly a cardiac rehabilitation program. (See "Pulmonary rehabilitation" and "Cardiac rehabilitation programs", section on 'Summary'.)

Vaccination — Annual vaccination against influenza and severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is indicated for patients with COPD and/or CVD. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'COVID-19 and influenza vaccination'.)

Vaccination against pneumococcus (pneumococcal polysaccharide vaccine [PPSV23, Pneumovax]) should be offered to individuals with COPD and CVD. Revaccination with PPSV23 is advised at approximately 10-year intervals. Vaccination with pneumococcal conjugate vaccine (PCV13, Prevnar) is individualized. Vaccination and revaccination schedules are described separately. (See "Pneumococcal vaccination in adults".)

Management of hypoxemia — Among patients with COPD, hypoxemia (eg, pulse oxygen saturation ≤88 percent) may be present at rest or be precipitated by exercise, sleep-related hypopneas, a fit of coughing, or noncompliance with home oxygen. When added to the limitations to blood flow caused by coronary stenoses, episodes of hypoxemia can contribute to myocardial ischemia. (See "Overview of the acute management of non-ST-elevation acute coronary syndromes", section on 'Oxygen'.)

The details of prescribing long-term oxygen therapy are provided separately. (See "Long-term supplemental oxygen therapy" and "Long-term supplemental oxygen therapy", section on 'Prescribing oxygen'.)

Effect of hypoxemia on the heart — The duration and extent of hypoxemia necessary to produce ischemic changes resulting from coronary lesions is unknown. Mild or brief hypoxemia appears to be unimportant. This was illustrated in a study of 38 patients with ST depression on cardiac stress testing in whom three minutes of breathing a hypoxic mixture to produce an arterial oxygen saturation of 85 percent did not amplify the electrocardiographic signs of ischemia [23]. Myocardial ischemia appears more likely to worsen when the duration of hypoxemia is longer than five minutes or the degree of hypoxemia is severe (pulse oxygen saturation [SpO₂] <85 percent) [24].

Hypoxemia may also increase the risk of cardiac arrhythmia. A high incidence of ventricular and supraventricular arrhythmia, particularly multifocal atrial tachycardia (MAT), has been described in patients with COPD with either stable disease or an acute exacerbation [25,26]. Arrhythmias in COPD are discussed separately. (See "Multifocal atrial tachycardia" and "Arrhythmias in COPD".)

Indications for supplemental oxygen — Supplemental oxygen therapy can correct hypoxemia that is associated with stable COPD or a COPD exacerbation. Supplemental oxygen therapy can also relieve hypoxic pulmonary vasoconstriction and reverse tissue hypoxia. The enhanced oxygen content of arterial blood maintains total body oxygen delivery and allows the cardiac output to fall, reducing left ventricular work. This latter effect is probably one of the reasons that long-term supplemental oxygen improves survival in patients with COPD [27-29]. (See "Long-term supplemental oxygen therapy", section on 'Benefits'.)

Interestingly, the benefit of oxygen in patients with moderate resting desaturation (89 to 93 percent) has been questioned [30]. In this study of 738 patients randomized to receive supplemental oxygen or no supplemental oxygen, there were no differences in time to death or first hospitalization.

Current indications for continuous long-term oxygen therapy include:

●PaO₂ ≤55 mmHg or SpO₂ ≤88 percent during rest

●PaO₂ between 56 to 59 mmHg (SpO₂ of 89 percent) combined with evidence of cor pulmonale, right heart failure, or erythrocytosis (hematocrit >56 percent)

●PaO₂ >60 mmHg or SpO₂ >90 percent with "compelling medical justification"; including significant coronary heart disease or active cardiac ischemia

Long-term oxygen therapy is discussed in detail elsewhere. (See "Long-term supplemental oxygen therapy".)

Oxygen supplementation may raise the PaCO₂ slightly in hypercapnic patients, but this is generally well tolerated. The risks of withholding oxygen or giving it too sparingly in these groups significantly outweigh any detrimental effects of higher PaCO₂ [27-29,31]. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

Noninvasive positive pressure ventilation — Noninvasive positive pressure ventilation (NPPV) can provide temporary ventilatory support in selected patients with acute cardiogenic pulmonary edema or acute hypercapnic respiratory failure due to a COPD exacerbation. It is an attractive option for patients who have severe dyspnea that may be due to COPD or CVD, buying additional time for diagnostic studies (eg, to determine whether symptoms are due to COPD, CVD, or both) and empiric therapy. (See "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications".)

TREATMENT OF COPD IN PATIENTS WITH CVD — The mainstays of treatment for COPD include the inhaled anticholinergic agents, inhaled selective beta-2 agonists, and inhaled glucocorticoids; roflumilast and theophylline are less commonly used. For patients with stable coronary artery disease (CAD), we treat symptomatic COPD with the same agents and doses that we would for someone without CVD, despite some concerns about increased CVD risk as noted below. (See "Stable COPD: Initial pharmacologic management".)

Inhaled anticholinergic medications — An inhaled short-acting anticholinergic (muscarinic) agent (eg, ipratropium) is suggested as an alternative to inhaled short-acting beta-adrenergic agonists (SABAs) or in combination with a SABA for acute symptoms of COPD. Long-acting anticholinergic agents (eg, aclidinium, glycopyrronium, tiotropium, umeclidinium) are recommended, regardless of underlying CVD, for patients with COPD who have frequent symptoms or exacerbations [1]. (See "Stable COPD: Initial pharmacologic management".)

Some studies have raised concern about a potential increase in cardiovascular risk with these agents, but other studies are reassuring. This concern should be balanced against the known benefits of these inhaled anticholinergic agents (eg, reduced frequency of exacerbations, fewer hospitalizations, and improved dyspnea). This topic is discussed in greater detail separately. (See "Role of muscarinic antagonist therapy in COPD" and "Role of muscarinic antagonist therapy in COPD", section on 'Cardiovascular effects'.)

Two systematic reviews and meta-analyses raised concerns that tiotropium, when administered by soft mist inhaler (eg, Spiriva Respimat), might be associated with increased mortality [32,33]. However, subsequent data from the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial was reassuring except for patients with unstable cardiovascular conditions who were excluded from the trial [34]. These studies are discussed in more detail separately. (See "Role of muscarinic antagonist therapy in COPD" and "Role of muscarinic antagonist therapy in COPD", section on 'Potential risks'.)

Beta-2 agonists — The inhaled beta-2 agonists (eg, albuterol, terbutaline, formoterol, indacaterol, olodaterol, salmeterol, vilanterol) are relatively selective for beta-2 adrenergic receptors. However, the possibility has been raised that mild beta-1 activity associated with these agents might cause the following adverse effects in patients with COPD and CVD:

●The possible induction of arrhythmias by stimulation of cardiac beta-adrenoreceptors

●Reflex activation of adrenergic mechanisms by causing peripheral vasodilation

●Downregulation of myocardial beta-2 receptors, potentially worsening heart failure associated with left ventricular systolic dysfunction

●Provocation of hypokalemia by intracellular translocation of potassium or hypoxemia through worsened matching of ventilation and perfusion

Short-acting beta-agonists — Short-acting inhaled beta-agonists (eg, albuterol, levalbuterol) are the preferred bronchodilators for treatment of acute symptoms of COPD, based on their rapid onset of action. This choice is unaffected by the presence of CAD. It is reassuring that among 12,090 patients age 55 or older with COPD, short-acting inhaled beta-agonists did not increase the risk of fatal or nonfatal myocardial infarction [35]. The management of acute exacerbations of COPD is discussed separately. (See "COPD exacerbations: Management", section on 'Hospital-based bronchodilator therapies'.)

Long-acting beta-agonists — Inhaled long-acting beta-agonists (LABAs) are widely used for treatment of COPD; data are generally reassuring regarding their safety in patients with CVD [36,37]. Several studies have specifically evaluated the cardiovascular effects of LABAs.

●Cardiovascular events – The Toward a Revolution in COPD Health (TORCH) trial compared salmeterol alone, fluticasone alone, salmeterol plus fluticasone, and placebo in 6112 patients with COPD over three years [38]. The frequency of cardiac events was not increased in the salmeterol alone group or the salmeterol plus fluticasone group [39]. In contrast, a nested case control study found an increased risk of cardiovascular events (ie, emergency department visit or hospitalization for coronary heart disease, cardiac arrhythmia, heart failure, or ischemic stroke) among 37,719 patients with COPD and new use of a LABA (adjusted OR 1.5, 95% CI 1.4-1.7), while prevalent use was associated with a 9 percent decrease in risk [40]. Similarly, a large database study of over 180,000 patients found that initiation of LABA, SABA, or ICS/LABA in patients with COPD was associated with increased risk for cardiovascular events compared with patients with COPD initiated on SAMAs, but not compared with those initiated on LAMAs [41].

There are some important limitations to these studies. The TORCH trial may not be widely generalizable due to exclusion of patients with underlying cardiovascular disease. In addition, the case-control and database designs are limited by potential confounding. Therefore, we advise caution when prescribing beta-agonists to people with severe and/or symptomatic coronary artery disease. Thorough patient characterization and risk stratification prior to the use of LABAs may reduce the risk of cardiovascular events in patients with coronary artery disease.

●Heart failure – Some but not all studies have suggested that beta-2 agonists may have an adverse effect in patients with left ventricular dysfunction. In a review of 1529 patients with left ventricular systolic dysfunction (by echocardiography or radionuclide ventriculography), the relative risk of hospitalization for heart failure followed a dose-response relationship with the use of inhaled beta-agonists [42]. In contrast, a retrospective study of 1294 subjects attending a heart failure disease management program did not find an increase in mortality associated with beta-2 agonist use (HR 1.0, 95% CI 0.8-1.4) after adjusting for age, sex, smoking, medications, and severity of co-morbidities [43].

●Arrhythmias – While beta-2 adrenergic agonists have the potential to increase heart rate and may increase cardiac arrhythmias via nonselective beta-adrenergic effects, a number of studies have shown a very low to no increased risk of serious arrhythmias with these medications. This is discussed in detail separately. (See "Arrhythmias in COPD", section on 'Beta-adrenergic agonists'.)

Combination LAMA-LABA — The combination of long-acting muscarinic agent (LAMA) plus a LABA is suggested as an initial regimen for patients with COPD with exacerbations or burdensome respiratory symptoms (algorithm 1). Data regarding cardiovascular safety of the individual agents are mixed, but largely reassuring [1,39,44], as described above. (See 'Inhaled anticholinergic medications' above and 'Long-acting beta-agonists' above.)

Data from clinical trials and systematic reviews of combination bronchodilator inhalers are more limited and not entirely consistent, suggesting heterogeneous effects in different trial populations:

●A systematic review comparing the combination of a LABA plus tiotropium with a LABA or tiotropium alone found no significant increase in serious adverse events with the combination inhaler, although separate data on cardiovascular outcomes was not provided [45].

●In a systematic review of trials comparing LAMA-LABA and LABA-glucocorticoid inhalers for stable COPD (11 studies, 9839 participants), a nonsignificant decrease in serious adverse events was noted in the LAMA-LABA group [46].

●However, another large systemic review (42 studies, over 71,000 patients with stable COPD) found that while dual LAMA-LABA therapy did not demonstrate increased risk for major adverse cardiac events compared with LAMA alone, LABA alone, or placebo, there was a small increased risk compared with combined LABA and inhaled glucocorticoid (1.6 versus 1.3 percent, RR 1.4, 95% CI 1.1-1.8) [47].

Combination inhaled bronchodilators plus glucocorticoid — The evidence suggests that the addition of inhaled glucocorticoids to LABAs or dual bronchodilator therapy is safe [38,39,47-52], albeit a small, not statistically significant, increase in cardiovascular risk has been reported with combined LABA and inhaled glucocorticoid therapy [47]. The following studies support this conclusion, although only the first one was specifically performed in patients with CVD [50]:

●In the three-year Study to Understand Mortality and MorbidITy (SUMMIT), the effect of fluticasone furoate-vilanterol (100 mcg-25 mcg) combination was compared with the individual components and placebo in 16,590 patients with moderate COPD (FEV₁ between 50 and 70 percent of predicted) and risk factors for or known CVD [50]. Relative to placebo, the combination inhaler did not affect all-cause mortality (hazard ratio [HR] 0.9, 95% CI 0.7-1.0) or composite cardiovascular events (HR 0.9, 95% CI 0.75-1.1).

●In a meta-analysis (10 studies, 10,680 participants) that compared combination inhaled LABA plus glucocorticoid with inhaled LABA alone in COPD, there was no significant difference in mortality (OR 0.9, 95% CI 0.8-1.1) [48]. However, underlying cardiovascular disease was an exclusion criterion for participation, and the rate of cardiovascular events was not examined.

●In the IMPACT and ETHOS trials of combination LAMA, LABA, and inhaled glucocorticoids in patients with stable COPD, there was reduced all-cause mortality in the groups receiving triple therapy compared with dual bronchodilator therapy alone [51,52]. (See "Role of inhaled glucocorticoid therapy in stable COPD", section on 'Mortality' and "Stable COPD: Follow-up pharmacologic management", section on 'Exacerbations on LAMA-LABA therapy'.)

Although not statistically significant, there was also a trend towards reductions in cardiovascular mortality in the triple therapy compared with dual therapy arm in both trials (0.5 versus 1.4 percent in ETHOS; 0.6 versus 1.0 percent in IMPACT).

●In a systemic review and meta-analysis, there was a similar risk of major adverse cardiovascular events in patients receiving triple therapy with LAMA-LABA-glucocorticoid compared with those receiving dual LAMA-LABA therapy (1.6 versus 1.8 percent, RR 0.8, 95%CI 0.6-1.2) based on three studies of nearly 14,000 patients [47]. However, patients receiving LAMA-LABA-glucocorticoid combination therapy did have increased rates of cardiovascular events compared with LABA-glucocorticoid alone (1.6 versus 1.4 percent, RR 1.3, 95% CI 1.0-1.7) in nine studies of 21,000 patients.

The roles of combined LABA-glucocorticoid and LAMA-LABA-glucocorticoid inhaled medications in COPD are discussed separately. (See "Stable COPD: Initial pharmacologic management", section on 'Alternative approaches' and "Stable COPD: Follow-up pharmacologic management", section on 'Persistent exacerbations with or without dyspnea'.)

Roflumilast — Roflumilast is a phosphodiesterase-4 inhibitor that is approved for use in patients with a history of COPD exacerbations. It provides a modest improvement in pulmonary function. Initial studies suggest that roflumilast does not substantially increase cardiovascular outcomes of death and nonfatal myocardial infarction but may increase the frequency of atrial fibrillation. As examples:

●In a pooled analysis of 14 trials lasting from 12 to 52 weeks, the composite endpoint of cardiovascular death, nonfatal myocardial infarction, and stroke was lower among patients receiving roflumilast compared with placebo (HR 0.65, 95% CI 0.45-0.9), although none of the individual components reached statistical significance [53].

●In a meta-analysis of eight trials (8696 patients), atrial fibrillation was more frequent in patients on roflumilast than placebo (0.4 versus 0.2 percent) [54]. Atrial fibrillation and other supraventricular arrhythmias occurred in less than 2 percent of patients in previous clinical trials with roflumilast, but these trials may not have included patients with known CVD.

●Concomitant administration of roflumilast and formoterol to healthy men did not result in adverse cardiovascular effects [55].

The use of roflumilast in COPD is discussed separately. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Phosphodiesterase-4 inhibitors (Roflumilast)'.)

Theophylline — Theophylline is generally avoided in patients with CAD. While occasionally used in patients with COPD for its mild bronchodilating effects and a possible improvement in exercise performance, it has a narrow therapeutic index and is associated with tachycardia and arrhythmias. Administration of theophylline is plagued by an appreciable incidence of side effects, even when serum drug concentrations are in the low therapeutic range. These adverse effects include tachycardia and palpitations, in addition to gastrointestinal upset and headaches. (See "Theophylline poisoning".)

Evidence of an adverse effect of theophylline in patients with CVD is largely indirect, but suggests an increased risk of dose-related atrial and ventricular arrhythmias [56-58]. The contribution of theophylline to the development of arrhythmias in patients with COPD is discussed separately. (See "Arrhythmias in COPD", section on 'Theophylline'.)

TREATMENT OF CVD IN PATIENTS WITH COPD — The management of symptomatic CAD in patients with COPD generally follows the same guidelines as for patients without COPD, except that we avoid nonselective beta-blockers in patients with COPD due to concerns about the induction of clinically important bronchoconstriction by nonselective agents. Instead, we typically use a cardioselective beta-blocker (eg, atenolol or metoprolol) [59]. Alternative agents for the treatment of ischemia, arrhythmias, or hypertension that do not carry the risk of bronchoconstriction can also be considered. (See "Chronic coronary syndrome: Overview of care" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".)

When initiating a selective beta-blocker in a patient with COPD, careful guidance should be given regarding new symptoms (eg, dyspnea, exercise intolerance, cough) or changes in medication use patterns (eg, increased need for a beta-agonist inhaler) that would prompt reevaluation.

The role of beta-blockers in patients with acute myocardial infarction is discussed separately. (See "Acute myocardial infarction: Role of beta blocker therapy", section on 'Contraindications'.)

Effects of beta-blockers on mortality and COPD exacerbations — Cardioselective beta-blocker therapy does not appear to worsen mortality in COPD patients, but the impact on exacerbations is less clear, particularly among those lacking cardiac indications.

In large trials of long-acting bronchodilator therapies, concomitant cardioselective beta-blocker therapy did not appear to reduce the respiratory benefits of inhaled long-acting beta-agonists [60,61]. In particular, the use of beta-blockers for cardiovascular indications did not impact rates of COPD exacerbations or mortality.

Observational data implicate a potential benefit for beta-blockade on these outcomes for some patients with COPD [62-67]; however, beta-blockade was not beneficial in a randomized trial in COPD patients without a cardiovascular indication [68]. Although the data in aggregate suggest a possible protective effect of beta-blockade in patients with COPD and cardiovascular disease, there may have been selection bias in observational studies based on patient selection for beta blocker use. Examples of studies in different settings include:

●Postmyocardial infarction – Among 10,884 patients with COPD discharged from Danish hospitals after an acute myocardial infarction, beta-blocker use was associated with a lower risk of acute exacerbation of COPD over at least a year of follow-up (multivariable-adjusted HR 0.78, 95% CI 0.74–0.83) independent of COPD severity or exacerbation history [69].

●Any indication for beta blockers – In an observational cohort study of 2230 COPD patients, the use of beta-blockers was associated with lower hazard ratios for both mortality (HR 0.68, 95% CI 0.56-0.83) and exacerbations of COPD (HR 0.71, 95% CI 0.60-0.83) [62].

●Patients without other indications – Five hundred and thirty two patients with moderate-severe COPD and no other indication for beta blocker therapy were randomly assigned to receive extended-release metoprolol or placebo [68]. The metoprolol group experienced an increased risk of exacerbation leading to hospitalization (92 versus 58 hospitalizations, rate ratio 1.6, 95% CI 1.1-2.4). This severe exacerbation risk was not mediated by changes in lung function or bronchodilator responsiveness in the metoprolol group [70]. Those taking metoprolol also had a time until first exacerbation of 202 days, versus 222 days among those not receiving metoprolol, a difference that did not achieve statistical significance (HR 1.05) [68].

Effect of cardioselective beta blockers on lung function — While nonselective beta blockade can precipitate bronchospasm in those who are predisposed, selective beta-1 blockers (eg, atenolol or metoprolol) are generally safe in patients with COPD, even when there is a bronchospastic component [59,62,71-76].

The effect of cardioselective beta-blockers was assessed in a meta-analysis of randomized trials in which single-dose or long-term cardioselective beta blockers were administered to nearly 400 patients with either asthma or COPD and reversible bronchoconstriction (>15 percent improvement in forced expiratory volume in one second (FEV₁) following bronchodilator treatment) [77]. The following results were noted:

●Single-dose use was associated with an 8 percent decrease in FEV₁, but a 5 to 9 percent increase in bronchodilator response

●Sustained use was not associated with a significant change in baseline FEV₁

●Long-term therapy did not increase respiratory symptoms or the use of inhaled beta-agonists

In a study of methacholine inhalation challenge in patients with COPD, propranolol (80 mg/day) caused a reduction in FEV₁ and in the bronchodilating effect of formoterol in addition to an increase in airway hyperresponsiveness to methacholine [78]. In contrast, metoprolol (100 mg/day) did not affect FEV₁ or responsiveness to formoterol but did increase airway hyperresponsiveness.

Effect of combination beta and alpha blockers on lung function — Combined beta and alpha blockers are sometimes indicated for patients with CAD and heart failure. (See "Beta blockers in the management of chronic coronary syndrome", section on 'Agents with alpha blocking activity'.)

Data regarding the effects of combined beta and alpha adrenergic blockade (eg, carvedilol, labetalol) in patients with COPD are limited, but include the following [79]:

●The effect of carvedilol (nonselective beta-blocker with alpha antagonism) on lung function was compared with the selective beta-blockers metoprolol and bisoprolol in 35 patients with COPD and heart failure [80]. FEV₁ was lowest with carvedilol and highest with bisoprolol (carvedilol 1.85 [95% CI, 1.67-2.03]; metoprolol 1.94 [95% CI, 1.73-2.14]; bisoprolol 2.0 [95% CI, 1.79-2.22]), although the six-minute walk distance was not different.

●In a small series of 11 patients with COPD and hypertension, labetalol (nonselective beta-blocker with alpha antagonism) up to 1200 mg/day caused no significant changes in FEV₁ or forced expiratory flow (forced expiratory flow [FEF] 25 to 75) [81]. Likewise, in a report of 14 patients with COPD treated with carvedilol 25 mg PO twice daily for heart failure, no changes were noted in FEV₁, vital capacity, or peak oxygen consumption with exercise [82].

●Celiprolol, a selective beta-1 blocker with mild beta-2 agonist and alpha-2 antagonist properties (not available in the United States), did not result in increased pulmonary symptoms, a decrease in FEV₁, or increased airway hyperresponsiveness to methacholine when given to four patients with mild-to-moderate COPD [78]. In the same study, FEV₁ was significantly lower after four days of propranolol, compared with metoprolol or placebo, and the bronchodilator response to formoterol was blunted after propranolol, but not metoprolol, celiprolol, or placebo.

Further study is needed to clarify the role of combined alpha and beta blockers in the management of cardiovascular disease (CVD) in patients with COPD.

Effect of statins on COPD exacerbations — Almost all patients with known CVD should be treated with a statin medication (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk"). While statins have been postulated to have an additional benefit of reducing COPD exacerbations, the evidence is conflicting [83-85]. (See "COPD exacerbations: Prognosis, discharge planning, and prevention", section on 'Ineffective interventions'.)

Revascularization in patients with COPD — The presence of COPD affects decision-making in patients with possible indications for coronary artery bypass grafting (CABG), because of concerns about excess postoperative morbidity and mortality in this population [86-89]. Expected post-CABG mortality ranges from 2 to 4 percent for all patients and is about 1 percent for those at lowest risk. Among 11,217 patients who underwent CABG, increasing severity of COPD based on impairment in FEV₁ correlated with an increasing frequency of postoperative complications and severe COPD was associated with early mortality, adjusted OR 2.31 (95% CI 1.23-4.36) [86]. In contrast to patients with severe COPD, post-CABG mortality for patients with mild or moderate COPD is similar to the rate among those without COPD [90]. In a database study from Taiwan of 706 individuals with COPD and almost 15,000 without, COPD did not increase the risk of mortality, but did increase the risk of postoperative pneumonia and acute respiratory failure [88]. (See "Early noncardiac complications of coronary artery bypass graft surgery".)

Patients with COPD who undergo CABG are also at increased risk of perioperative morbidity, particularly pulmonary complications that result from sternotomy and use of cardiopulmonary bypass [86,91]. Patients with significant COPD who survive the early postoperative period after CABG appear to have improved quality of life [91].

For patients who require CABG, preoperative and postoperative optimization of pulmonary function and careful monitoring for rhythm disturbances seem advisable. If available, minimally invasive CABG may represent a useful therapeutic option, although it has not been specifically assessed in patients with COPD. (See "Strategies to reduce postoperative pulmonary complications in adults" and "Coronary artery bypass surgery: Perioperative medical management" and "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use" and "Early cardiac complications of coronary artery bypass graft surgery", section on 'Arrhythmias'.)

Among patients with CVD and COPD, percutaneous coronary interventions (eg, balloon angioplasty or stent placement) are associated with an increased mortality and rates of repeat revascularization within one year compared with patients without COPD [15].

●Using the National Heart, Lung, and Blood Institute Dynamic Registry, the outcomes following percutaneous coronary interventions were compared in patients with (860) or without (10,048) COPD. Patients with COPD had a significantly increased risk of death (hazard ratio 1.30, 95% CI 1.01-1.67). Of note, patients with COPD were also significantly less likely to be prescribed beta-blockers at discharge.

●In an analysis of over 4600 cases comparing bare-metal stents with drug-eluting stents, patients with COPD had higher rates of major adverse cardiac events (15.2 versus 8.1 percent), all-cause death (11.7 versus 2.4 percent), cardiac death (5.7 versus 1.2 percent), MI (3.5 versus 1.9 percent), stent thrombosis (2.5 versus 0.9 percent), and major bleeding (4.2 versus 2.1 percent) [92]. In all instances the drug-eluding stent patients had better outcomes than the bare-metal patients suggesting that drug-eluting stents be used in patients with COPD.

Although outcomes after percutaneous coronary intervention (PCI) or CABG have not been directly compared in patients with COPD, PCI is a reasonable alternative for some patients who would otherwise receive a recommendation for CABG. We suggest that the decision to choose one revascularization therapy be made after the patient has been fully informed of the relative benefits and risks of each approach.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

SUMMARY AND RECOMMENDATIONS

●Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) share tobacco abuse as a risk factor and commonly coexist. The presence of either disease can adversely affect outcomes of the other. (See 'COPD/CVD relationship' above.)

●In patients with concomitant severe COPD and CAD, a number of nonpharmacologic therapies (eg, smoking cessation, pulmonary rehabilitation, vaccination against influenza and pneumococcus, supplemental oxygen) are indicated to reduce symptoms, improve quality of life, and prevent exacerbations, as in patients with COPD alone. (See 'Nonpharmacologic therapies' above.)

●In general, the pharmacologic management of comorbid COPD and cardiovascular disease (CVD) follows the same guidelines as for patients without comorbid disease. (See 'Treatment of COPD in patients with CVD' above and 'Treatment of CVD in patients with COPD' above.)

●For patients with COPD and CAD, we recommend that a short-acting bronchodilator be prescribed for use as-needed for relief of acute symptoms of COPD (Grade 1B). Either a short-acting beta-agonist, a short-acting anticholinergic, or a combination can be used, depending on patient preference. For patients on a long-acting anticholinergic agent, a short-acting beta-agonist is used instead of a short-acting anticholinergic agent, for quick relief of COPD symptoms. (See 'Short-acting beta-agonists' above and 'Inhaled anticholinergic medications' above and "Stable COPD: Initial pharmacologic management", section on 'Rescue bronchodilator therapy for all patients'.)

●Concern has been raised regarding possible adverse cardiovascular effects of the inhaled long-acting beta-agonists (LABAs) and also the long-acting anticholinergic medications (LAMAs), although the data is largely reassuring. For patients with concomitant COPD and CVD, we advise following guideline-based therapy for COPD; many patients with COPD require therapy with both agents. (See 'Treatment of COPD in patients with CVD' above.)

●The use of combination long-acting beta-agonist-glucocorticoid inhalers does not adversely affect mortality in COPD, although data are limited regarding specific effects on cardiovascular outcomes. (See 'Combination inhaled bronchodilators plus glucocorticoid' above.)

●For patients with COPD and comorbid CVD, we recommend using a cardioselective beta blocker (eg, atenolol or metoprolol), rather than a nonselective beta-blocker (Grade 1B). For those patients who also have heart failure, use of a combined beta and alpha blocker (eg, carvedilol, labetalol) appears to have minimal adverse effect on COPD, although data are limited. (See 'Effect of cardioselective beta blockers on lung function' above and 'Effect of combination beta and alpha blockers on lung function' above.)

●Cardioselective beta-blocker therapy does not appear to worsen mortality in COPD patients, but the impact on exacerbations is less clear, particularly among those lacking cardiac indications. (See 'Effects of beta-blockers on mortality and COPD exacerbations' above.)

●After initiation of beta-blocker therapy, patients are given careful guidance regarding new symptoms (eg, dyspnea, exercise intolerance, cough) or increased need for a beta-agonist inhaler that should prompt reevaluation. (See 'Treatment of CVD in patients with COPD' above.)

●For patients with severe COPD who meet cardiovascular criteria for coronary artery bypass grafting (CABG), percutaneous coronary intervention is often preferred if there is a reasonable likelihood of success. (See 'Revascularization in patients with COPD' above.)

●For those who require CABG, preoperative optimization of pulmonary function and careful monitoring for cardiac arrhythmias are advised. A minimally invasive surgical approach may be advisable. (See "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use", section on 'Patient selection'.)