β‐Blockers and Chronic Obstructive Pulmonary Disease: Inappropriate Avoidance?

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and is often accompanied by one or more comorbid conditions. While there are established morbidity and mortality benefits of β‐blocker (BB) use for certain cardiovascular conditions, data suggest that clinicians are often reluctant to prescribe them in the presence of COPD because of concerns for bronchoconstriction, despite evidence that they are typically well‐tolerated among these patients. Treatment guidelines for COPD are consistent with those for cardiovascular disease management and support the role of BBs in management of particular cardiovascular conditions, even in the presence of severe COPD. Adherence to these guidelines could result in significant decreases in morbidity and mortality among patients with COPD. Additionally, current treatments for COPD are often linked to increased cardiovascular disease events. Further study is needed to clarify and guide therapeutic management in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a common disease and the third leading cause of death in the United States.1, 2 Comorbid conditions that increase the risk of hospitalization and mortality occur frequently and are important factors in both the prognosis and functional capabilities of patients with COPD.1, 3 Numerous observational studies recognize the increased likelihood of cardiovascular conditions and have found that patients with COPD are 3 times as likely to have heart failure (HF) and twice as likely to have coronary artery disease (CAD).1 In a recent review of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), patients with COPD had higher prevalence of cardiovascular disease (CVD), hypertension, and diabetes.3 Studies also associate airflow obstruction with subclinical atherosclerosis as represented by either increased carotid intima‐media thickness or ankle‐brachial index.4 In addition, current treatments for COPD are linked to increased cardiovascular risk and events.2 The primary cause of hospitalizations for COPD is CVD, not respiratory failure, and these patients have increased mortality in HF and post–myocardial infarction (MI) when compared with those without COPD.3, 5, 6, 7 Whether these associations are caused by the disease process, shared risk factors (eg, smoking), systemic inflammation, chronic infections, or other factors is unclear; however, they amplify the need for particular attention to cardiovascular risk managment.3

β‐Adrenergic blockers (BBs) are indicated and considered standard of care for many of the cardiovascular conditions that often accompany COPD, including HF, atrial fibrillation (AF), CAD, and hypertension. Evidence clearly supports the value of BBs in reducing morbidity and mortality among patients with a history of MI or HF. While BBs may not be the preferred initial class for treatment of hypertension, most patients with these other cardiovascular conditions have hypertension as a concurrent or contributing risk factor. However, particularly for patients with COPD, the issues surrounding medication use are complex, and current evidence is far from translation into clinical practice. Historically, fear of potential respiratory adverse effects has led clinicians to avoid BB use in these patients and evidence‐based therapies for cardiovascular conditions are clearly underutilized. Current drug utilization review and medication therapy management programs may further perpetuate apprehension and encourage avoidance. We continue to receive patient‐specific notifications warning of the potential for “inappropriate therapy–drug‐disease interaction” in patients with COPD receiving a BB for an appropriate indication.

Pharmacologically and physiologically, blocking β₂ adrenoceptors could theoretically lead to bronchoconstriction and worsening lung function. The possibility of precipitating bronchospasm, likely translated from the increase in airway resistance and decrease in ventilation capacity observed in patients with asthma, has discouraged BB use and created controversy in the treatment of COPD. Despite this potential, mounting evidence suggests that BBs are generally well‐tolerated in patients with COPD and may actually lead to improved survival and paradoxical improvements in bronchial responsiveness.5, 8, 9, 10 Mechanistically, BBs may improve pulmonary hemodynamics by enhancing cardiac function as well as specific beneficial effects on lung inflammation and β₂ adrenoceptor density.5

Large observational and epidemiological studies consistently show that many still do not receive these lifesaving medications; only one third to one half of patients with COPD and an evidence‐based indication for a BB receive such therapy.5, 7, 11 This inappropriate avoidance may contribute to the overall burden of disease and detrimental health outcomes for many patients with COPD. In our preliminary review of the ARIC population, while BB use reduced the incidence of MI or CAD, only 18% of participants with COPD received this therapy.12 Out of concern for this issue, we explore the role of BBs in CVD management in patients with COPD as well as the potential effects of COPD treatments on cardiovascular morbidity and mortality.

BBs in Cardiovascular Disease

Heart Failure

In several large clinical trials, metoprolol succinate, carvedilol, and bisoprolol have demonstrated a reduction in morbidity and mortality in patients with systolic HF when added to baseline angiotensin‐converting enzyme (ACE) inhibitor therapy.13, 14, 15 These agents provide protection from (and reversal of) the deleterious effects of chronic adrenergic stimulation, a major determinant of the progressive clinical course of HF. Long‐term benefits include improved left ventricular (LV) ejection fraction and diastolic function as well as a potential decrease in the risk of sudden cardiac death.13 Current guidelines recommend that the majority of patients with reduced LV systolic function be treated with one of these BBs even in the presence of concomitant COPD, diabetes, or peripheral vascular disease.13, 14, 15 Guidelines also note that the medications used to treat each condition (ie, BBs and β₂‐agonists) potentially interact, which may lead to decreased prescribing and/or patient nonadherence.13 COPD independently contributes to poor outcomes in HF, yet the presence of COPD is the most significant reason for patients failing to receive adequate treatment for HF.13, 16

Coronary Artery Disease

BB therapy is considered standard of care post‐MI.17, 18 Most trials supporting this recommendation were published in the 1980s, prior to the routine use of antiplatelet agents and percutaneous intervention.17 More recent studies have demonstrated a potential reduction in mortality, reinfarction, or ventricular fibrillation post‐MI with use of carvedilol or metoprolol succinate, although the primary endpoints were not significantly reduced by allocation to a BB.17, 18 Similarly, in a recent observational study, BB therapy did not reduce the primary cardiovascular endpoint in patients with a remote MI history, CAD without MI history, or CAD risk factors only.19 Based on previous affirmative evidence, a class I recommendation remains for acute and long‐term BB use in post‐MI patients with reduced LV function.17, 18 In those with normal LV function or without hypertension, guidelines recommend BB use for up to 3 years after a cardiac event.18 BBs are also first‐line agents for symptomatic relief of stable angina, with an option of a calcium channel blocker (CCB) or long‐acting nitrate in patients intolerant to BBs.20 Current guidelines state that treatment with selective BBs, potentially initiating at a reduced dose, is considered safe with coexisting CAD and COPD.16, 17

Atrial Fibrillation

BBs are useful for rate control in patients with AF and are recommended as first‐line initial therapy.21 They may be used in combination with a nondihydropyridine CCB (verapamil, diltiazem) and/or digoxin for patients with uncontrolled heart rate and persistent AF.21 While BBs will not convert AF to normal sinus rhythm, they can effectively maintain normal sinus rhythm. They are also effective in maintaining sinus rhythm in post‐cardiac surgery patients.21 Patients with COPD have an increased incidence of AF, and treatment can be challenging because of the breathlessness and disability that result from both of these disease states.16 While there are alternatives for rate control, BBs should not be avoided unnecessarily; however, guidelines recommend initiating therapy with a CCB rather than a BB in patients with obstructive lung disease (class IC).21

Hypertension

Historically, BBs have been widely used as antihypertensive agents and remain among the most commonly prescribed medications. A meta‐analysis of 13 trials comparing BBs with other antihypertensive agents or placebo revealed a higher risk of stroke and no difference in MI in patients taking BBs.22 With the availability of newer classes (ie, diuretic, ACE inhibitor, angiotensin receptor blocker [ARB], CCB) and evidence of more favorable outcomes, BBs are no longer generally promoted as first‐line therapy for hypertension.22 The most prevalent cardiovascular comorbidity in COPD is likely hypertension, which has implications for COPD prognosis.16

BBs in COPD

Analogous to earlier safety concerns and avoidance of BBs in HF, patients with COPD have typically been excluded from most randomized placebo‐controlled trials evaluating BB treatments. Recognition of the benefit of BBs in patients with COPD began to emerge almost 15 years ago when a retrospective review identified a mortality risk reduction with BB treatment after MI. The benefit observed in COPD (40% risk reduction) was similar to that observed for BB use in HF.23 While no long‐term randomized controlled trials have been performed to definitively prove the benefits of BBs in patients with COPD, retrospective and observational data continue to point to improved survival and decreased hospitalizations with use of these medications.5, 10, 11 The benefits from BB use in patients with COPD may be independent of their value in CVD. Other effects may balance the potential adverse effects of noncardioselective and higher‐dose cardioselective BBs and confer systemic, cardiac, and pulmonary benefits.24 Animal models suggest that chronic BB use leads to a paradoxical improvement in bronchial responsiveness and pulmonary hemodynamics through upregulation of lung β‐receptor density, reduction of lung inflammation and mucous secretion, and enhancement of cardiac function.25, 26 Future research is needed to clarify the pathways and mechanisms of relevance for the benefits of BBs on COPD in humans.5

In retrospective and observational analyses, both cardioselective and noncardioselective BBs appear to decrease mortality in COPD patients with and without overt CVD, including those with hypertension, HF, and atherosclerosis, as well as those undergoing major vascular surgery.6, 10, 24, 27, 28 BBs may improve health outcomes by reducing patient symptoms, reducing the incidence and severity of noninfectious COPD exacerbations, and enhancing exercise capacity.5, 10, 29 Additionally, patients with existing CVD and newly diagnosed COPD have a higher mortality rate with BB discontinuation.5, 10 However, these patients, especially those with severe COPD, remain less likely to receive a BB or may be prescribed lower doses of BBs than those without COPD.6, 7, 30

Prospective studies reviewing BB effects on respiratory function have been small, short in duration, and narrow in focus. Most have concentrated on defining the differences among the established BBs in HF—the cardioselective agents bisoprolol and metoprolol and the noncardioselective, α‐blocking agent carvedilol.31, 32, 33, 34, 35 In a prospective study designed to evaluate the safety of cardioselective BBs in patients with CAD and COPD, no significant decrease in forced expiratory volume in 1 second (FEV₁) was observed with conventional or controlled‐release metoprolol at maximal doses.31 Another small study randomized elderly patients with HF and moderate to severe COPD to bisoprolol or placebo, titrated to maximum tolerated doses. While bisoprolol was associated with a significant reduction in FEV₁, the mean number of COPD exacerbations was similar, and reversibility and static lung volumes were not impaired.32 To determine whether cardioselectivity affects lung or vascular function in patients with HF, carvedilol, metoprolol succinate, and bisoprolol were compared in a randomized, open‐label, triple‐crossover study. The BB switches were well‐tolerated in patients with COPD, although there were demonstrable changes in airway function, with FEV₁ being lowest with carvedilol and highest with bisoprolol. BB use did not decrease the effectiveness of β₂‐agonists.33 In a double‐blind superiority trial comparing titration to target doses of bisoprolol and carvedilol in elderly patients with heart failure, neither drug was superior in respect to tolerability. The presence of COPD did not limit dosage titrations. Pulmonary adverse events occurred more frequently in the carvedilol group (eg, change in FEV₁, bronchospasm) compared with bisoprolol but did not lead to withdrawal or dosing limitations.34 Bisoprolol and carvedilol were compared again among elderly patients with HF and moderate to severe COPD in a randomized open‐label study. Patients receiving bisoprolol had fewer adverse events and a significant increase in FEV₁ vs carvedilol. Respiratory side effects did not typically result in the need for BB discontinuation.35 The tolerability of BBs shown in these analyses does not support the recommendation for adjustment of BB dosing in patients with COPD.

Although coupled with inherent limitations, retrospective and observational data also support the overall lack of detrimental effects of BB therapy in COPD and even provide evidence of potential benefits of this therapy. A subgroup study of an original cohort of vascular surgery patients found that BBs were not associated with any impairment in health‐related quality of life among patients with COPD and peripheral arterial disease.36 Another retrospective cohort study using a disease‐specific database examined the effect of BBs in the management of COPD when added to established treatments for COPD. After a mean follow‐up of 4.35 years, there was an overall 22% reduction in mortality with BB use, with additive benefits and no deleterious impact on lung function associated with BBs at all treatment steps for COPD.9 The results of a meta‐analysis of retrospective cohort studies in patients with COPD were consistent with a protective effect of BBs on all‐cause morality, similar to the magnitude seen with statins. The authors note that it is unclear whether the protective effect is a class effect or differs based on receptor selectivity.8 Most recently, a retrospective analysis of patients in a large HF registry having an index hospitalization compared differences in outcomes between those with and without COPD receiving cardioselective and noncardioselective BBs. Endpoints of 60‐ to 90‐day mortality and mortality or rehospitalization were analyzed. BBs were associated with lower risk‐adjusted mortality in all patients with no evidence of any association between selectivity and outcomes.24 In general, these findings do not support current recommendations for the preferential use of cardioselective BBs.

Contrary to previous beliefs, BBs do not appear to increase the rate of COPD exacerbations or mortality.27, 29, 37 In fact, several observational studies demonstrate a mortality reduction with both cardioselective and nonselective BB use during COPD exacerbations.5, 10, 11 In a meta‐analysis of randomized, blinded, controlled trials, cardioselective BBs produced no significant change in FEV₁, the incidence of COPD exacerbations, or the treatment response to β₂‐agonists compared with placebo.37 A retrospective review of patients admitted with an acute exacerbation of COPD compared those who received BBs with those who did not. Inpatient BB use was well‐tolerated and associated with reduced mortality.38 An observational cohort study assessed the long‐term effect of BB use on survival and exacerbations in COPD patients with and without CVD. Hypertension was the primary reason for BB use in patients without other overt CVD comorbidities. Improved survival and reduced risk of exacerbations were observed similarly across the population.10 In a retrospective cohort study of patients with ischemic heart disease, HF, or hypertension who were hospitalized for an acute exacerbation of COPD, no association was found between BB treatment and in‐hospital mortality, 30‐day readmission, or late mechanical ventilation. There was a difference between selective and nonselective BBs, however, with nonselective use associated with an increased risk of 30‐day readmission.11

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines specifically address CVD management in patients with COPD (highlighted in the Table). These guidelines generally recommend that patients with HF, ischemic heart disease, AF, and hypertension be treated as usual per respective guidelines as evidence does not suggest treating them differently.16 The use of BBs in patients with ischemic heart disease or HF, including those with severe COPD, is warranted as the morbidity and mortality benefits outweigh the potential risk. The GOLD guidelines also support the use of BBs in AF, although with the availability of other options, a trial of another medication class might be reasonable. Lastly, BBs can be used in patients with hypertension as an adjunct to first‐line agents. In all cases, the use of cardioselective BBs is recommended over other BBs.16 In the future, these recommendations may reflect the lack of evidence for treatment based on selectivity.6, 24

Table 1.

Recommendations for Use of BBs in CVD and COPD

Condition	Effects of BBs	Recommendations in COPDa
Heart failure	Decrease sympathetic nervous system effects on heart Reduce morbidity and mortality in systolic HF	Use in patients with systolic HF, as tolerated
Coronary artery disease	Reduce morbidity and mortality acutely post‐MI Symptomatic relief of stable angina	Use in hemodynamically stable patients post‐MI, as tolerated May use BBs, CCBs, or nitrates for symptomatic angina
Atrial fibrillation	Rate control Maintain sinus rhythm	May use BBs, CCBs, or digoxin
Hypertension	Potential increase in stroke, no effect on MI risk No longer first‐line agents	Use first‐line agents (ie, diuretics, CCBs, ACE inhibitors, ARBs) before BBs

Abbreviations: ACE, angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; BB, β‐blocker; CCB, calcium channel blocker; COPD, chronic obstructive pulmonary disease; CVD, cardiovascular disease; HF, heart failure; MI, myocardial infarction.

^aCardioselective preferred in all conditions per guideline recommendations.

COPD Treatments and Cardiovascular Disease

While the value of BBs in improving CVD outcomes for patients with COPD is apparent, the effects of treatments for COPD on pulmonary or CVD outcomes are less clear. The inhaled β₂‐agonists (IBAs), anticholinergics (IACs), and corticosteroids (ICSs) are the preferred and most commonly prescribed medications for COPD. Although these medications are generally well‐tolerated and improve quality of life, lung symptoms, and frequency of exacerbations, they have no meaningful effect on the progression of COPD.16, 39 These treatments at best only marginally modify COPD mortality risk, and IBAs and IACs are increasingly associated with cardiovascular risk, further complicating patient prognosis.2, 16, 39, 40, 41

Concerns for exacerbation of CVD continue to be recognized with both long‐acting and short‐acting IBAs and IACs. Pharmacologically, IBAs stimulate sympathetic control while IACs suppress parasympathetic tone, potentially increasing the risk of tachyarrhythmias, myocardial ischemia, stroke, and death.2 Data evaluating the risk of CVD stem from clinical trials, meta‐analyses, and retrospective, observational, and case‐control studies in which cardiovascular morbidity and mortality are secondary outcomes. The results are frequently conflicting, fraught with controversy, and contain numerous confounders. Debates continue as increased risk of cardiovascular events with IBAs and IACs is suggested by meta‐analyses and observational studies, while randomized clinical trials indicate no increase in risk.2, 40, 41, 42, 43, 44 In contrast, ICSs appear to have neutral or potentially positive effects on MI and cardiovascular death.45

Guidelines have previously recognized the risk of increased cardiovascular events with use of long‐acting IBAs.39 The evaluation of cardiovascular safety with short‐acting IBAs is more limited, although studies suggest an association.2 Risk of adverse effects is typically increased with the use of higher doses.16 β₂‐Adrenergic stimulation can result in resting sinus tachycardia with the potential for cardiac rhythm disturbances in susceptible individuals. Arrhythmias can occur, possibly as a result of the initial decrease in serum potassium observed with these agents.16, 41 The risk of clinically significant arrhythmias appears to be rare and decreases over time.2, 16 In a recent population‐based retrospective cohort, using a nested case‐control approach, the rate of cardiac arrhythmias was modestly elevated with the new use of short‐acting and long‐acting IBAs.46 In contrast, in a recent randomized, double‐blind, placebo‐controlled trial in patients with moderate to severe COPD, a long‐acting IBA did not increase the risk of cardiovascular events. Rates were similar with use of a long‐acting IBA, ICS, IBA‐ICS combination, or placebo, although having a history of MI doubled the probability of a cardiovascular event.47

Most recently, in a nested case‐control analysis of a retrospective cohort study, increased cardiovascular risk was associated with new use of long‐acting IBAs and IACs. In this group of older individuals with COPD, events appeared to be highest in the first few weeks after the medication was prescribed, with no evidence of differing cardiovascular risk between the medication classes. New use was associated with increased hospitalization or emergency department visit for a cardiovascular event, specifically for acute coronary syndrome and HF but not cardiac arrhythmia or stroke. In secondary analyses, IACs were found to have a protective effect for stroke.2 While there is a potential association between IBA use and HF hospitalization and mortality, these agents may conversely improve HF exacerbations, with potential benefits caused by improved pulmonary function and cardiovascular hemodynamics.48

For IACs, a meta‐analysis initially identified an increase in major adverse cardiovascular outcomes with longer duration of use of tiotropium and ipratropium (48 weeks to 24 months vs 6 weeks to 6 months).39, 43 Shortly thereafter, a large randomized trial and a subsequent meta‐analysis reported a reduced risk of MI and no difference in risk for stroke associated with tiotropium.42, 44 A more recent retrospective, population‐based, nested case‐control study identified a nonsignificant but slightly elevated risk of arrhythmias with the use of ipratropium, with effects waning over time.46 In a direct comparison and mixed treatment meta‐analyses, the tiotropium Respimat Soft Mist inhaler (solution delivered) was associated with a significantly increased risk of overall and cardiovascular mortality compared with the dry powder tiotropium HandiHaler, a long‐acting IBA, an IBA‐ICS combination, or placebo.49 The tiotropium HandiHaler formulation, IBA, and IBA‐ICS combination had relatively safer profiles, with the lowest risk of overall death in patients receiving the IBA‐ICS combination.49

Inhaled bronchodilator medications prescribed for as‐needed or on a regular basis are central to symptom management in COPD. The GOLD guidelines generally do not recommend altering COPD treatment strategies with coexisting HF, ischemic heart disease, AF, or hypertension as there is no direct evidence that patients should be treated differently.¹³ For patients with ischemic heart disease or AF, the guidelines state that it is reasonable to avoid high doses of IBAs. Obtaining appropriate heart rate control may also be more difficult in patients with AF using high doses of IBAs. Patients with severe HF who are using IBAs should receive close monitoring by their healthcare providers due to the potential for increased mortality and hospitalizations.16 Based on recent studies and guideline recommendations, the tiotropium Respimat Soft Mist inhaler should be used with caution.16, 49

Conclusions

BBs have established morbidity and mortality benefits in several cardiovascular conditions that frequently coexist with COPD. Many of these patients do not receive BB therapy because of concerns for bronchoconstriction. Ample evidence suggests that these agents are typically well‐tolerated in COPD patients and may reduce CVD and COPD mortality as well as COPD exacerbations. Current guidelines for COPD are consistent with those for CVD management and support the role of BBs for treatment of particular cardiovascular conditions, with preference for the use of cardioselective agents. Further complicating patient management, recent studies tend to link cardiovascular risks with treatments for COPD. These findings highlight the need for close monitoring with use of IBAs and IACs and suggest that patients should be warned of and monitored for the onset of cardiovascular events, particularly when initiating new bronchodilator therapy. Additional research is needed to further define the benefits of BB therapy and guide the treatment of patients with COPD and CVD.

Disclosure

The authors have no conflicts of interest or financial disclosures to declare.

J Clin Hypertens (Greenwich). 2013;15:925–930. DOI: 10.1111/jch.12204. ©2013 Wiley Periodicals, Inc.