Appraisal of β-Blocker Use in Patients with Cardiovascular Disease and Chronic Obstructive Pulmonary Disease

Abstract

β-blockers are a fundamental component of cardiovascular disease (CVD) management, while β₂-agonists are used to treat chronic obstructive pulmonary disease (COPD). Current guidelines recommend that these conditions be treated as usual, even when they coexist. However, there have been concerns over COPD exacerbation risk with β-blockers and attenuation of the beneficial effects of β₂-agonists in this comorbid population, leading to β-blocker underuse. Recent evidence suggests that β-blockers, particularly cardioselective β-blockers, do not increase COPD exacerbations, demonstrate good efficacy and safety, and improve survival in patients with COPD after first-time myocardial infarction. In atrial fibrillation with COPD, both cardioselective and nonselective β-blockers may be associated with a lower COPD exacerbation risk than calcium channel blockers, as well as improving outcomes and reducing mortality risk. In this review, we summarize the β-blocker prescribing patterns in patients with CVD and COPD; describe the reasons for β-blocker underuse in patients with CVD with COPD; collate up-to-date evidence on the effects of β-blockers on symptoms and outcomes in each of these comorbid populations; and review the current treatment guidelines for coexisting COPD and CVD to support the rational prescribing of β-blockers. Finally, we provide recommendations for future research needed to demonstrate the clinical rationale of prescribing β-blockers and to encourage the generation of more robust evidence-based guidelines for β-blockers use. Future large-scale, prospective, randomized controlled trials are needed to expand the body of evidence and better understand the effects of β-blockers in CVD with comorbid COPD.

Key Points

β-blockers are underused in patients with cardiovascular disease (CVD) and concurrent chronic obstructive pulmonary disease (COPD) because of the perceived risk of worsening COPD.

This review of evidence emphasizes that β-blockers, particularly cardioselective β-blockers, are associated with improved outcomes, including reduced mortality, in patients with CVD and COPD.

While further research is needed, the current evidence encourages the rational use of cardioselective β-blockers in patients with CVD and COPD.

Introduction

Cardiovascular diseases (CVDs) are associated with sympathetic nervous system activation. β-blockers, which inhibit sympathetic nervous system activation, are a fundamental component of guideline-recommended CVD treatment. β-blockers are classified as first-generation (nonselective, blocking both β₁- and β₂-adrenoreceptors), second-generation (more selective for β₁ [cardioselective]), or third-generation (very selective for β₁ [highly cardioselective]). β-blockers reduce CVD events through β-adrenoreceptor blockade, decreasing heart rate, blood pressure, and oxygen demand [1]. Table 1 [2–8] shows the most commonly used β-blockers and their CVD indications.

Table 1.

Indications for commonly used β-blockers [2–8]

Agent	Generation/receptor selectivity	Indication	Off-label uses	References
Metoprolol	Second-generation cardioselective (β1)	Angina, HF, MI, atrial flutter/AF, and hypertension	Supraventricular tachycardia and thyroid storm	Morris et al. 2023 [2]
Bisoprolol	Second-generation cardioselective (β1)	HF with reduced ejection fraction, ischemic heart disease, and hypertension in many countries	–	Feng et al. 2023 [3] AlHabeeb et al. 2022 [4]
Nebivolol	Third-generation cardioselective (β1)	HF with reduced ejection fraction, ischemic heart disease, and hypertension in many countries	–	Ferri et al. 2021 [5] Olawi et al. 2019 [6] Cicero et al. 2018 [7]
Carvedilol	Third-generation nonselective β1 and β2	Chronic HF with reduced ejection fraction, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients	Stable angina, AF, and ventricular arrhythmia	McTavish et al. 1993 [8]

AF atrial fibrillation, HF heart failure, MI myocardial infarction

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by airflow obstruction [9]. It is one of the most common comorbidities of CVD, and its presence worsens CVD prognosis [10]. COPD coexists with CVDs such as hypertension, myocardial infarction, heart failure, ischemic heart disease, and atrial fibrillation (AF). One study reported a higher CVD prevalence in patients with COPD than in those without (59.6% versus 28.4%) [11]. The estimated prevalence of heart failure with COPD is 13–39%, of ischemic heart disease with COPD is nbetween < 20% and > 60%, and of arrhythmia is 10–15% [12–14]. Cardiovascular events are a leading cause of hospitalization in patients with COPD. One study showed that up to 50% of hospital admissions were due to CVD in patients with mild-to-moderate COPD [15]. Another showed that heart failure and myocardial infarction were the leading causes of hospitalization in patients with COPD [16]. Inhaled β-agonist bronchodilators, which activate cyclic adenosine monophosphate pathways and relax airway smooth muscle, are the mainstay COPD therapy [17].

There are conflicting views about whether β-adrenoreceptors should be blocked in CVD patients with COPD, leading to β-blocker underuse [18–20], despite guidelines recommending their use even when these conditions coexist. The reasons for underuse include concerns about β-blocker-induced COPD exacerbation [21, 22] and concerns that β-blockers may restrict the protective effects of β₂-agonists in COPD and induce bronchospasm [23]. However, this appears to be mostly associated with nonselective β-blockers [23, 24], which block both β₁ and β₂-adrenoreceptors; therefore, they compete with β₂-agonists, in turn interfering with their bronchodilatory effects. Nevertheless, cardioselective β-blockers have been developed, which have a higher affinity for β₁- than β₂-adrenoreceptors [25] and are considered to have less influence on β₂-agonist activity. Nevertheless, the best treatment approach for CVD with COPD remains a challenging controversy.

This review summarizes β-blocker prescribing patterns in this comorbid population; describes the controversies around β-blocker use and the reasons for underuse; collates up-to-date evidence on the effects of β-blockers in specific CVDs with COPD; and reviews current treatment guidelines for concurrent CVD and COPD to provide evidence-based recommendations on the rational prescription of β-blockers.

Narrative Review Methods

The PubMed database was screened for clinical studies that were published in English between March 2004 and March 2024. The inclusion criteria were human studies on β-blockers, CVDs, and COPD. The search string was: (“hypertension” OR “blood pressure” OR “systolic” OR “diastolic” OR “cardioselective” OR “dose” OR “treatment guidelines”) AND (“beta-blocker” OR “bisoprolol” OR “metoprolol” OR “carvedilol” OR “nebivolol”) AND (“arrhythmia, cardiac” OR “coronary artery disease” OR “cardiomyopathy” OR “heart failure” OR “myocardial ischemia” OR” myocardial infarction” OR “atrial fibrillation” OR “acute coronary syndrome” OR “vascular disease” OR “cardiovascular risk” OR “heart rate” OR “heart disease management” OR “airflow obstruction”) AND (“pulmonary disease, chronic obstructive” OR “respiratory insufficiency” OR “pulmonary function” OR “respiratory failure” OR “dyspnea” OR “lung health”).

From this search, 37 articles were identified, of which 21 articles met the inclusion criteria. Major COPD and CVD guidelines and guidelines on the use of β-blockers in patients with CVD and COPD were also reviewed. Additional relevant studies that were published after March 2024 were also identified and included using an ad hoc approach.

β-Blocker Prescribing Patterns

Heart Failure and COPD

The intersection of COPD and heart failure as coexisting conditions is ill-defined in terms of treatment [26]. In a retrospective cohort of patients with heart failure (n = 15,778), COPD (n = 27,927), and heart failure with COPD (n = 4768) from 2010 to 2018, β-blocker use was initially lower for concurrent COPD/heart failure than heart failure alone (69.3% versus 74.0%), but this difference progressively declined by 2018 [26]. These findings support that COPD in patients with heart failure once deterred clinicians from prescribing β-blockers; however, this trend may be declining.

Myocardial Infarction and COPD

Rasmussen et al. evaluated whether β-blockers are underused after first-time myocardial infarction in 13,496 patients with COPD and determined the temporal trends and risk factors for nonuse [27]. After myocardial infarction, patients with COPD were less frequently prescribed β-blockers than those without (53.2% versus 76.2%). Throughout 1995–2015, COPD remained a significant predictor for β-blocker nonuse. Risk factors for nonuse included increasing age, female sex, and increased COPD severity (e.g., frequent exacerbations). Although β-blocker use increased throughout the study, they were still underused, indicating clinicians’ reluctance to prescribe to patients with COPD.

AF and COPD

Benson et al. emphasized that real-world studies have demonstrated significant β-blocker underuse in AF with COPD [28]. They investigated temporal trends in β-blocker use following AF diagnosis in the hospital setting in patients with concomitant COPD (12.1%) and determined the clinical factors associated with β-blocker use. Overall, 264,180 patients were enrolled across the 21-year period (1995–2015, inclusive). Fewer patients with COPD used β-blockers after AF diagnosis (38.8% versus 53.2% without COPD). β-blocker use increased in both groups during the study, but the proportion was consistently lower among those with COPD, although the difference was smaller during the last year studied (2015: 55.5% versus 61.6% in COPD versus non-COPD, respectively), illustrating underuse. Of note, a recent analysis of the GLORIA-AF registry found that, in patients with AF, the presence of COPD was associated with reduced use of β-blockers (adjusted hazard ratio: 0.79) [29].

Reasons for β-Blocker Underuse in CVD with COPD

Recent reviews have highlighted the ongoing uncertainty regarding best practices for β-blocker prescribing in CVD with COPD [19, 30]. It has been suggested that β-blockers should be avoided in patients without overt CVD as they can worsen health status, reduce lung function, and increase COPD-related hospitalization [30]. Although β₁-selective agents appear to have more favorable effects on forced expiratory volume in 1 second and respiratory symptoms and no impact on the clinical effects of β₂-agonists [24, 31], one study suggested that the β₁-selective agent metoprolol should not be used in those without an indication for β-blockers [19]. Two clinical studies have pinpointed the adverse effects of metoprolol in COPD patients. A prospective randomized trial [21] of patients with a clinical history of COPD with moderate airflow limitation and an increased exacerbation risk showed that metoprolol was associated with a higher exacerbation risk leading to hospitalization. This trial was terminated early owing to the futility of reaching the primary endpoint, as well as ongoing safety concerns. Similarly, the BLOCK-COPD study found that metoprolol was associated with a higher COPD exacerbation risk—underpinned by forced vital capacity bronchodilator responsiveness at baseline—and was associated with a 60% higher rate of severe/very severe exacerbation [22]. Thus, inappropriate use of β-blockers in patients without a cardiovascular indication may increase COPD exacerbation risk. This concern regarding COPD exacerbation risk with β-blockers has contributed to their underuse. Regarding bisoprolol, a recent study by Devereux et al. reported that bisoprolol in patients with COPD at high risk of exacerbation did not increase the risk of COPD exacerbation relative to the placebo, and that 27% of patients reached the maximum bisoprolol dose of 5 mg/day [32]. Additional research is necessary to determine the optimal dose and management of each type of β-blocker in patients with COPD.

Effects of Β-Blockers on Clinical Outcomes in Specific CVDs with Comorbid COPD

Despite previous studies demonstrating concern over COPD exacerbation risk with β-blockers [21, 22], recent evidence suggests that patients with COPD with a CVD indication for β-blockers may achieve certain overall benefits. Table 2 [18, 24, 33–50] summarizes the effects of commonly used β-blockers on the symptoms and outcomes of patients with specific CVDs with comorbid COPD. Here, we summarize the take-home messages of these studies.

Table 2.

Summary of studies on the symptom and outcome effects of β-blockers in specific CVDs with coexisting COPD [18, 24, 33–50]

CVD	Publication	Population	Intervention/comparator	Key results	Conclusions
Hypertension	Au et al. [45]	Hypertension and COPD	β-blocker versus CCB	β-blockers decreased all-cause mortality (HR 0.57)	β-blockers are beneficial in COPD, preexisting cardiac disease, and hypertension
	Cazzola et al. [46]	Hypertension and mild-to-moderate COPD	Nebivolol versus nifedipine	BP reduced with both treatments; FEV1 reduced with nebivolol but not nifedipine; nebivolol safe over 2 weeks	Nebivolol in patients with hypertension and mild-to-moderate COPD safe over 2 weeks
HF	Jabbour et al. [24]	Chronic HF and COPD	Metoprolol versus carvedilol versus bisoprolol	FEV1 highest with bisoprolol, followed by metoprolol and carvedilol, respectively	Switching between cardioselective and nonselective β-blockers resulted in changes in airway function in COPD
	Kubota et al. [35]	HFrEF and COPD	Cardioselective versus nonselective β-blocker versus nonuse	Heart rate lower in β-blocker groups versus nonuse; 2-year all-cause/cardiovascular mortality lower with nonselective β-blockers versus nonuse, but not with cardioselective β-blockers versus nonuse	Nonselective β-blockers reduced all-cause/cardiovascular mortality in HFrEF and COPD
	Sessa et al. [36]	HF and COPD and diabetes mellitus	Metoprolol versus carvedilol	HF hospitalization risk 38% lower with metoprolol than carvedilol at 1 year; no difference in survival or COPD hospitalization	HF hospitalization risk increased with carvedilol, but no difference in survival or COPD hospitalization risk
	Hawkins et al. [37]	HF and moderate/severe COPD	Bisoprolol versus placebo	FEV1 reduced after 4 months of bisoprolol compared with placebo, but reversibility following inhaled β2-agonists not impaired by bisoprolol; exacerbations similar; symptoms/quality of life not impaired by bisoprolol	Bisoprolol in HF and moderate/severe COPD reduced FEV1; symptoms and quality of life not impaired
	Lainscak et al. [38]	Chronic HF and COPD	Bisoprolol versus carvedilol	Bisoprolol increased FEV1 compared with baseline and reduced heart rate and had fewer adverse events than carvedilol; adverse events in 19% of patients with bisoprolol versus 42% with carvedilol	β-blockers caused adverse events in chronic HF and COPD; bisoprolol improved pulmonary function and had fewer adverse events than carvedilol
	Liao et al. [39]	Chronic HF and COPD	Metoprolol versus bisoprolol versus carvedilol versus nonuse	Only bisoprolol reduced mortality and decreased hospitalization due to chronic HF exacerbation; no association between β-blocker use and COPD exacerbation	In chronic HF and COPD, bisoprolol reduced mortality and hospitalization compared with carvedilol and metoprolol
	Andersson et al. [40]	Right-sided HF and COPD	β-blocker (selectivity not specified) versus nonuse	HR for mortality with β-blockers 0.90 versus nonuse	β-blockers reduced mortality in right-sided HF and COPD
	Higuchi et al. [41]	Acute HF (LVEF < 50%) with/without COPD	β-blocker (selectivity not specified) in patients with versus without COPD	β-blockers associated with lower all-cause mortality with (HR 0.39) and without (HR 0.62) COPD due to lower noncardiac mortality, which persisted in those with COPD after multivariate adjustment (HR 0.40) owing to lower noncardiac (but not cardiac) mortality	β-blockers associated with lower all-cause mortality in HF + COPD owing to lower noncardiac mortality
	Mentz et al. [47]	HF and COPD	Cardioselective or nonselective β-blocker in patients with versus without COPD	Cardioselective and nonselective β-blockers associated with lower risk-adjusted mortality with and without COPD; β-blocker selectivity not associated with different outcomes with versus without COPD	β-blocker selectivity not associated with differences in outcomes with versus without COPD
	Su et al. [48]	HF and COPD	Metoprolol versus bisoprolol versus carvedilol versus nonuse	Metoprolol and carvedilol: no survival benefit compared with nonuse; bisoprolol: survival benefit compared with nonuse (HR 0.76)	In HF and COPD, bisoprolol, but not metoprolol or carvedilol, had a dose–response survival benefit
MI	Rasmussen et al. [18]	First-time MI and COPD	β-blocker versus nonuse	β-blocker use associated with lower acute COPD exacerbation risk (adjusted HR 0.78)	β-blocker use not associated with increased acute COPD exacerbation risk following MI, independent of COPD severity, symptom burden, and exacerbation history
	Wang et al. [33]	First-time acute MI and COPD	Cardioselective or nonselective β-blocker versus nonuse	Cardioselective β-blockers reduced mortality compared with nonuse (HR 0.93); nonselective β-blockers did not increase mortality compared with nonuse (HR 0.98)	β-blockers, particularly cardioselective, improved survival among COPD patients after first MI
	Chung et al. [34]	First-time MI and COPD	Bisoprolol versus carvedilol	Cardioselective β-blocker (bisoprolol) had lower incidences of mortality (HR 0.93), major adverse cardiovascular and cerebrovascular events (HR 0.96), HF hospitalization (HR 0.84), and major adverse pulmonary events (HR 0.94)	Cardioselective β-blockers had a lower incidence of severe events than nonselective β-blockers (carvedilol)
	Su et al. [49]	Acute MI and COPD	β-blocker versus NDCCB versus control	β-blockers had a lower overall mortality risk (adjusted HR 0.91 versus NDCCBs; 0.88 versus control) and decreased re-hospitalization risk for COPD and other respiratory diseases	β-blockers reduced mortality in COPD after acute MI and did not increase COPD exacerbation risk
AF	Rodríguez-Mañero et al. [42]	AF with/without COPD	β-blocker in patients with versus without COPD	All-cause mortality twofold higher with versus without COPD (28.3% versus 15.5%); β-blocker nonuse independent predictor of all-cause mortality	β-blockers reduced mortality in AF with and without COPD
	Vlachopoulou et al. [43]	AF and COPD	Cardioselective versus nonselective β-blocker	Cardioselective and nonselective β-blockers had similar all-cause mortality (adjusted HR 1.10), cardiovascular mortality (adjusted HR 1.33), and hospitalization (adjusted HR 1.65)	No difference between cardioselective and nonselective β-blockers in clinical outcomes
	Lin et al. [44]	AF and COPD	β-blocker versus CCB	COPD exacerbation risk lower with β-blockers (HR 0.80 versus CCBs); after COPD severity stratification, reduction in exacerbations with β-blockers persisted in mild (HR 0.75) but not severe (HR 0.95) COPD	β-blockers in mild COPD and AF associated with lower exacerbation risk than CCBs; close β-blocker monitoring in severe COPD and AF necessary
	Bucci et al. [50]	AF and COPD	β-blocker (selectivity not specified) versus nonuse	Reduced association between COPD and mortality with β-blocker use (HR 0.94) than without β-blocker use (HR 6.23)	β-blockers in COPD and AF associated with a lower mortality risk than without β-blockers

AF atrial fibrillation, BP blood pressure, CCB calcium channel blocker, COPD chronic obstructive pulmonary disease, CVD cardiovascular disease, FEV₁ forced expiratory volume in 1 second, HF heart failure, HFrEF heart failure with reduced ejection fraction, HR hazard ratio, LVEF left ventricular ejection fraction, MI myocardial infarction, NDCCB nondihydropyridine calcium channel blocker

General CVD and COPD

A systematic review of 15 studies (participant numbers ranging from 208 to 41,814) on β-blockers in patients with CVD with COPD found that β-blockers were associated with a 28% mortality reduction and a 37% reduction in COPD exacerbations; however, the majority of the included studies did not specify the β-blocker type or dose, instead referring to β-blockers generally, and the specific types of mortality were also not distinguished [51]. It is possible that adjustments to the dose of β-blockers may influence the risk of COPD exacerbations; however, the absence of β-blocker dose data requires careful interpretation of the available evidence. Karimi et al. evaluated whether the association between β-blocker use and COPD exacerbation risk differed between patients with and without a cardiovascular indication (hypertension, ischemic heart disease, AF, and/or heart failure at baseline) for β-blocker use [52]. In patients with CVD, cardioselective β-blockers significantly reduced COPD exacerbation risk, whereas in patients without a cardiovascular indication, cardioselective β-blockers were not associated with an altered COPD exacerbation risk. These findings suggest that β-blockers reduce mortality and COPD exacerbations in patients with CVD generally and COPD.

Hypertension and COPD

Given the clinical complexity of this population, β-blockers are usually part of a broader antihypertensive regimen, tailored to minimize adverse pulmonary effects while effectively controlling blood pressure [53]. In hypertension with comorbid COPD, clinicians prescribe cardioselective β-blockers to reduce bronchospasm risk [21]. It has been shown that nonselective β-blockers increase COPD exacerbation risk in patients with COPD and hypertension [52], presumably because they also block the β₂-adrenoreceptor, leading to airway constriction, while cardioselective β-blockers significantly reduce COPD exacerbation risk [52]. Additionally, newer β-blockers may be a safer option for patients with hypertension and COPD [46]. Overall, appropriate cardioselective β-blocker selection can effectively manage hypertension in patients with COPD without lung function deterioration or COPD exacerbation, supporting their safety.

Myocardial Infarction and COPD

Evidence suggests that cardioselective β-blockers significantly improve survival rates in myocardial infarction. Wang et al. investigated the association between β-blockers and mortality in 23,116 patients with COPD after first-time acute myocardial infarction (with β-blockers, n = 7609 [32.9%]; without β-blockers, n = 15,507 [67.1%]). β-blockers, particularly selective β-blockers, improved overall survival [33]. Furthermore, when evaluating which β-blocker types had better efficacy and safety in patients with COPD and myocardial infarction (cardioselective, n = 7247 [49.0%] versus nonselective, n = 7542 [51.0%]), cardioselective β-blockers had a lower incidence of all-cause mortality, major adverse cardiovascular and cerebrovascular events, heart failure hospitalization, and major adverse pulmonary events in patients with COPD after myocardial infarction [30]. Specifically, bisoprolol (cardioselective) had a lower incidence of all-cause death, major adverse cardiovascular events, and cerebrovascular events than carvedilol (nonselective) [34].

Rasmussen et al. investigated whether β-blockers were associated with acute COPD exacerbation risk after myocardial infarction [18]. In their Danish registry, 10,884 patients with COPD were discharged after first-time myocardial infarction. The 1-year acute exacerbation rate was 35%, and among those alive and free from exacerbations at 1 year, 61.5% were using β-blockers. β-blockers (both cardioselective and nonselective) were associated with a significantly lower acute COPD exacerbation risk than nonuse in the overall study population at 90 days and 1 year, supporting their safety.

Taken together, the evidence suggests that β-blockers—particularly cardioselective β-blockers—have good efficacy and safety, do not increase COPD exacerbations in myocardial infarction patients with COPD, and improve survival.

Heart Failure and COPD

Kubota et al. evaluated the impact of cardioselective β-blockers on the long-term outcomes of 412 patients with heart failure with reduced ejection fraction and COPD [35]. Cardioselective β-blockers were used in 149 patients (36%), nonselective β-blockers in 124 (30%), and no β-blockers in 139 (34%). Heart rate was higher in the no β-blocker group than in the β-blocker groups. Cardiovascular mortality was lower in the nonselective β-blocker group, but for patients treated with cardioselective β-blockers, no significant reduction in cardiovascular mortality was observed. Furthermore, one study suggested that cardioselective agents (metoprolol and bisoprolol) are preferred over nonselective agents (carvedilol) in heart failure with concurrent COPD; however, carvedilol still seems to be widely used in this context [54]. Supporting this view, Sessa et al. compared survival, heart failure hospitalization risk, and COPD hospitalization risk between carvedilol and metoprolol in geriatric patients with heart failure and COPD [36]. No significant differences in survival or COPD hospitalization were observed between metoprolol and carvedilol, but carvedilol users had a 38% higher heart failure hospitalization risk at 1 year. Moreover, in patients with chronic heart failure and COPD, forced expiratory volume in 1 second was higher with bisoprolol than with metoprolol and carvedilol [24], and bisoprolol significantly increased forced expiratory volume in 1 second compared with baseline, reduced heart rate, and had fewer adverse events than carvedilol [37]. Furthermore, in patients with chronic heart failure and COPD, bisoprolol reduced mortality risk and decreased the rate of hospitalization due to chronic heart failure exacerbation compared with carvedilol and metoprolol [38]. Bisoprolol has also demonstrated a survival benefit compared with nonuse in patients with heart failure and comorbid COPD [39].

Right heart failure is one of the most important COPD complications. Andersson et al. followed patients with COPD and right heart failure prescribed β-blockers for the risk of all-cause death between 1995 and 2015 [40]. Of these patients, 24% used β-blockers, which was associated with reduced mortality. Moreover, in a multicenter observational cohort study, Higuchi et al. evaluated the association of β-blockers with mortality in hospitalized patients with comorbid COPD and acute heart failure (left ventricular ejection fraction < 50%) [41]. β-blockers were associated with lower all-cause mortality, regardless of COPD.

Overall, β-blockers appear to reduce mortality in heart failure with comorbid COPD, with cardioselective agents showing better safety than nonselective carvedilol.

AF and COPD

β-blockers potentially reduce mortality in patients with COPD and AF. Rodríguez-Mañero et al. evaluated the clinical outcomes and prognosis of patients with comorbid COPD and AF [42], in whom β-blockers reduced all-cause mortality risk. Moreover, in their post hoc analysis of the MISOAC-AF randomized trial, Vlachopoulou et al. evaluated the outcomes of recently hospitalized patients with AF with comorbid COPD treated with cardioselective versus nonselective β-blockers; there was no difference in clinical outcomes between cardioselective and nonselective β-blockers [43].

β-blockers affect COPD-related symptoms in AF patients with comorbid COPD differently on the basis of COPD severity. Lin et al. evaluated the acute exacerbation risk of patients with COPD stratified by severity with comorbid AF who were treated with β-blockers compared with patients treated with calcium channel blockers from 2009 to 2018 [44]. β-blockers in patients with COPD and AF were associated with a lower COPD exacerbation risk than calcium channel blockers, with a hazard ratio of 0.75 in patients with mild COPD and 0.95 in patients with severe COPD; therefore, close monitoring of β-blocker use in severe COPD with AF is encouraged. Furthermore, Bucci et al. conducted a prospective observational study in five Asian-Pacific countries on patients with COPD and AF and found that the risk of mortality was reduced with β-blockers [50].

These findings suggest that β-blockers—both cardioselective and nonselective—improve outcomes and reduce mortality risk in patients with AF with COPD. In addition, they may be associated with a lower COPD exacerbation risk than calcium channel blockers.

Current Guidelines for β-Blocker Use

Table 3 [55–64] summarizes the guidelines on COPD and CVD treatment (separately) with β-agonists and β-blockers, respectively. Here, we synthesize the guidelines that address the nuanced use of β-blockers in the management of coexisting CVD and COPD as a recommendation on how β-blockers should be correctly used in COPD.

Table 3.

Review of guidelines for the treatment of CVDs and COPD separately [55–64]

Condition		Guideline Source	Recommendation	CoR	LOE
CVD	Hypertension	2023 European Society of Hypertension Guidelines for the Management of Arterial Hypertension [57]	To prevent AF in hypertension, β-blockers may be considered in combination with renin–angiotensin system blockers	II	B
			To treat hypertension in AF, β-blockers are the preferred drug class for heart rate control	I	B
			When treating hypertension in AF, β-blockers should not be combined with NDCCBs	III	C
		2024 European Society of Cardiology Guidelines for the Management of Elevated Blood Pressure and Hypertension [55]	Among all blood pressure-lowering drugs, ACE inhibitors, ARBs, dihydropyridine CCBs, and diuretics (thiazides and thiazide-like drugs such as chlorthalidone and indapamide) have demonstrated the most effective reduction blood pressure and cardiovascular events, and are therefore recommended as first-line treatments to lower blood pressure	I	A
			It is recommended that β-blockers are combined with any of the other major blood pressure-lowering drug classes when there are other compelling indications for their use, e.g., angina, post-myocardial infarction, HF with reduced ejection fraction, or heart rate control	I	A
			In patients with a history of myocardial infarction who require blood pressure-lowering treatment, β-blockers and RAS blockers are recommended as part of treatment	I	A
			In patients with symptomatic angina who require blood pressure-lowering treatment, β-blockers and/or CCBs are recommended as part of that treatment	I	A
			In patients with symptomatic HFreF/HFmrEF, the following treatment with blood pressure-lowering effects are recommended to improve outcomes: ACE inhibitors (or ARBs if ACE inhibitors are not tolerated) or angiotensin receptor-neprilysin inhibitors, β-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter type 2 inhibitors	I	A
	STEMI	American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines [59]	In patients with STEMI without signs of HF or evidence of a low-output state, increased risk for cardiogenic shock, or other contraindications, β-blockers should be initiated in the first 24 h	I	B
			β-blockers should be continued during and after hospitalization for all patients with STEMI and with no contraindications to their use	I	B
			Patients with initial contraindications to β-blockers in the first 24 h after STEMI should be reevaluated to determine their subsequent eligibility	I	C
			It is reasonable to administer β-blockers at the time of STEMI presentation in patients with no contraindications who are hypertensive or have ongoing ischemia	IIa	B
	NSTE-ACS	AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes [60]	In non-STEMI, β-blockers should be initiated within the first 24 h when there are no signs of HF, evidence of a low-output state, an increased risk of cardiogenic shock, or other contraindications	I	A
			In patients with concomitant NSTE-ACS, stabilized HF, and reduced systolic function, it is recommended to continue β-blockers with either metoprolol, carvedilol, or bisoprolol	I	C
			Patients with contraindications to β-blockers in the first 24 h of NSTEMI should be reevaluated to determine sequent eligibility	I	C
			It is reasonable to continue β-blockers in patients with normal LV function with NSTEMI	IIa	C
	Pre-HF	2022 ACC/AHA Joint Committee on Clinical Practice Guidelines [61]	In pre-HF, in patients with a recent/remote history of myocardial infarction or acute coronary syndrome and LVEF fraction ≤ 40%, β-blockers reduce mortality	I	B-R
	HFpEF	The Korean Society of Heart Failure Guidelines [62]	β-blockers may reduce cardiovascular mortality	IIb	C
	HFmrEF	The Korean Society of Heart Failure Guidelines [62]	β-blockers may reduce cardiovascular mortality	IIb	C
		2022 ACC/AHA Joint Committee on Clinical Practice Guidelines [61]	Among patients with current/previous symptomatic HFmrEF (LVEF 41–49%), β-blockers reduce the risk of HF hospitalization and cardiovascular mortality	IIb	B-NR
	HFrEF	The Korean Society of Heart Failure Guidelines [62]	β-blockers are considered part of the standard of care for reducing symptoms, cardiovascular mortality, and heart failure hospitalization	I	A
			β-blockers reduce mortality in randomized clinical trials, including bisoprolol, carvedilol, and metoprolol	I	A
			In patients aged ≥ 70 years, nebivolol may be beneficial	IIa	B
		2022 ACC/AHA Joint Committee on Clinical Practice Guidelines [61]	In HFrEF with current or previous symptoms, use of one of the three β-blockers proven to reduce mortality (bisoprolol, carvedilol, metoprolol) is recommended to reduce mortality and hospitalization	I	A
			In HFrEF with current or previous symptoms, β-blockers provide high economic value	Value statement: high value (A)
	AF	2023 ACC/AHA/American College of Clinical Pharmacy/Heart Rhythm Society Guidelines for the Diagnosis and Treatment of Atrial Fibrillation [58]	In AF with a rapid ventricular response but stable hemodynamics, β-blockers are recommended for acute rate control	I	B-R
			In pregnant individuals with persistent AF, β-blockers with a record of safety in pregnancy (e.g., propranolol and metoprolol) are reasonable as first-line agents	2a	B-NR
COPD	Prevention of COPD exacerbations	The Department of Veterans Affairs and Department of Defense [63]	If the diagnosis is confirmed but the patient is not having an acute exacerbation, prevention and risk reduction methods (e.g., smoking cessation and patient education) are offered first	NA	NA
		The American Thoracic Society [64]	In COPD with dyspnea or exercise intolerance, LABA/LAMA combination therapy is recommended over monotherapy	Strong	Moderate
	Treatment for acute exacerbations	Global Initiative for Chronic Obstructive Lung Disease [56]	SABAs are recommended as the initial bronchodilators to treat acute COPD exacerbation		C
		The Department of Veterans Affairs and Department of Defense [63]	If the patient presents to primary care with acute exacerbation, initiate SABA If symptoms resolve, consider continuing SABA therapy or initiating LABA, steroid, or antibiotic therapy	NA	NA
	Treatment for patients with previous exacerbations	Global Initiative for Chronic Obstructive Lung Disease [56]	Patients with 0–1 moderate exacerbations (not hospitalized) should be treated with a bronchodilator if the mMRC score is 0–1 and CAT score is < 10, or a LABA/LAMA if the mMRC score is ≥ 2 and CAT score is ≥ 10	NA	NA
			For ≥ 2 moderate exacerbations or ≥ 1 exacerbation leading to hospitalization, a LAMA is recommended if the mMRC score is 0–1 and CAT score is < 10, and LAMA, LAMA + LABA, or ICS + LABA is recommended if the mMRC score is ≥ 2 and the CAT score is ≥ 10. After, a review, assess, adjust approach is adopted	NA	NA
		The Department of Veterans Affairs and Department of Defense [63]	If the patient is chronically symptomatic and/or has a moderate to severe exacerbation in the past year, use SABA with the following to increase intensity: first-line LAMA; add LABA for severe symptoms; add ICS only for continued moderate to severe exacerbations
		The American Thoracic Society [64]	If dyspnea/exercise intolerance despite dual therapy, triple therapy with ICS/LABA/LAMA is recommended in patients with a history of ≥ 1 exacerbation in the past year or hospitalization	Conditional	Moderate
			In patients with COPD receiving triple therapy, ICS can be withdrawn if no exacerbations in the past year	Conditional	Moderate

ACE angiotensin-converting enzyme, AF atrial fibrillation, ARB angiotensin receptor blocker, B-NR level of evidence B with data derived from nonrandomized trials or meta-analyses of such trials, B-R level of evidence B with data derived from randomized trials or meta-analyses of such trials, CAD coronary artery disease, CAT COPD Assessment Test, CCB calcium channel blocker, CoR class of recommendation, HF heart failure, HFmrEF heart failure with mid-range ejection fraction, HFpEF heart failure with preserved ejection fraction, HFrEF heart failure with reduced ejection fraction, ICS inhaled corticosteroid, LABA long-acting β-agonist, LAMA long-acting muscarinic antagonist, LOE level of evidence, mMRC modified Medical Research Council, NA not applicable, NSTEMI non-ST-segment elevation myocardial infarction, RAS renin–angiotensin system, SABA short-acting β-agonist, STEMI ST-segment elevation myocardial infarction

Hypertension and COPD

The Global Initiative for COPD [56] suggests that hypertension in patients with COPD should be treated as usual, as should COPD, even when they coexist. The 2023 European Society of Hypertension guidelines for arterial hypertension management [57] emphasize that hypertension is the most common comorbidity in patients with COPD, and hypertension and CVD are associated with increased cardiovascular event risks [65]. Hypertension management in COPD should consider the effects of antihypertensive drug classes on impaired respiratory function, including COPD exacerbations, as well as the interactions between antihypertensive drugs and bronchodilators used to treat COPD [65]. On the basis of a systematic review and meta-analysis of 49 studies involving more than 670,000 patients with COPD and CVD, the guidelines suggest that β-blockers (both cardioselective and nonselective) reduce heart rate and all-cause mortality compared with nonuse. Moreover, β₁-selective agents reduce COPD exacerbations in patients with CVD [66]. Therefore, the guidelines recommend that, in patients with COPD, hypertension and CVD should be treated with β₁-selective blockers to reduce mortality and COPD exacerbations [57].

Ischemic Heart Disease/Heart Failure and COPD

The Global Initiative for COPD [56] suggests that there is no evidence that chronic or acute heart failure should be treated differently in the presence of COPD; therefore, usual heart-failure guidelines should be followed. Treatment with β₁-selective agents improves heart failure survival; however, despite evidence showing that their use in COPD is safe, they do not tend to be prescribed [57]. Similarly, ischemic heart disease should be treated according to guidelines, irrespective of COPD.

AF and COPD

In COPD with severe and worsening dyspnea, AF may be a trigger or a consequence of acute exacerbation; in this context, bronchodilators are considered proarrhythmic [67]. Moreover, although evidence suggests an overall acceptable safety profile for long-acting β₂-agonists [68], caution is advised for short-acting β₂-agonists, which may precipitate AF [69]. Despite this understanding, the Global Initiative for COPD guidelines [56] state that AF should not alter COPD treatment. In AF with comorbid COPD, the 2023 American College of Cardiology/American Heart Association guidelines state that it is reasonable to use cardioselective β-blockers for AF rate control, especially where other indications exist, such as myocardial infarction and heart failure (recommendation: 2a; level of evidence: B-R [randomized]) [58].

Guideline Summary

There is no evidence that in patients with COPD and a CVD indication, β-blockers either reduce the benefits of treatment with long-acting β₂-agonists or increase cardiovascular risk [56]. Guidelines recommend that CVD and COPD should be treated as usual, even when they coexist, and cardioselective β-blockers may be preferred. Therefore, clinicians should pay attention to these guidelines to inform the rational use of β-blockers in this population.

Future Directions

Further studies are required to evaluate the effects of highly cardioselective β-blockers that could be superior to metoprolol in treating patients with comorbid CVD and COPD. Bisoprolol is one candidate that has demonstrated several benefits (Table 2); however, dose-optimization studies on bisoprolol in comorbid CVD and COPD are lacking. Robust dose–response data are needed for all β-blockers to determine the effects of β-blockers in patients with COPD. Additionally, there is a need for further evidence regarding the safety of β-blockers in patients experiencing COPD exacerbations. Although a randomized parallel-group placebo-controlled trial found that bisoprolol treatment did not increase the risk of COPD exacerbations [32], results for other β-blockers are still needed. In the absence of such data supporting the safety of β-blocker treatment during COPD exacerbations, a cautious approach to β-blockers would be advised, including the temporary discontinuation of β-blockers. There is also an urgent need for additional large-scale, prospective, randomized, controlled studies on patients with COPD with specific CVDs to better understand the effects of this drug class by CVD type when it coexists with COPD, rather than studying CVDs as a whole. Finally, evidence-based dedicated treatment guidelines tailored specifically for patients with specific CVDs and COPD are required to address the unique challenges posed by these populations.

Conclusions

β-blockers have several indications in CVD treatment, while β₂-agonists are a mainstay treatment for COPD. Although earlier evidence suggested that β-blockers increase COPD exacerbation risk, guidelines generally suggest that CVD and COPD should be treated as usual, even when they coexist. More recent studies show that β-blockers, particularly cardioselective β-blockers, do not increase COPD exacerbation risk and improve patient outcomes in those with a CVD indication; however, β-blockers remain underused. Future large-scale, prospective, randomized controlled trials are needed to increase clinicians’ confidence in the rational prescribing of β-blockers and to produce evidence-based treatment guidelines for this comorbid population.

Declarations

Funding

This work was supported by funding from the Clinical Research Foundation of the Cardiovascular Society of the Chinese Medical Association and the 2022–2024 Guangdong Basic and Applied Basic Research Foundation to the authors’ institutions, Guangdong National Science Foundation (Nos. 2022A1515012161, 2022A1515010227, 2023A1515011794, 2024A1515010458) and by Merck Serono Co., Ltd, Beijing, China.

Conflict of interest

Q.Y. is an employee of Merck Serono Co., Ltd, China (an affiliate of Merck KGaA Darmstadt, Germany). All other authors report no conflict of interest.

Ethics approval

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Availability of data and material

No new data were generated or analyzed in support of this research.

Code availability

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Author contributions

All authors were involved with the conception and design of this manuscript, the drafting and critical revision of the manuscript, and final approval of the manuscript.