Practical recommendations for the use of beta-blockers in chronic obstructive pulmonary disease

Abstract

Introduction:

Controversies regarding the use of beta-blocker in COPD have been longstanding and based on inconsistent data. COPD and cardiovascular disease have many shared risk factors and potentially overlapping pathophysiologic mechanisms. Beta-blockers, a mainstay of treatment in ischemic heart disease, congestive heart failure, and cardiac arrhythmia, remain underutilized in COPD patients despite considerable evidence of safety. Furthermore, observational studies indicated potential benefits of beta-blockers in COPD via a variety of possible mechanisms. Recently, a randomized controlled trial of metoprolol versus placebo failed to show a reduction in COPD exacerbation risk in subjects with moderate to severe COPD and no absolute indication for beta-blocker use.

Areas Covered:

Physiology of beta-adrenergic receptors, links between COPD and cardiovascular disease, and the role for beta-blockers in COPD management are discussed.

Expert Opinion:

Beta-blockers should not be used to treat COPD patients who do not have conditions with clear guideline-directed recommendations for their use. Vigilance is recommended in prescribing these medications for indications where another drug class could be utilized.

Introduction:

There has long been controversy and uncertainty regarding the use of beta-blocker medications in patients with chronic obstructive pulmonary disease (COPD). Many practitioners are concerned about potentially inducing bronchospasm or decreasing the efficacy of beta-agonist medications with the use of beta-blocker medications in obstructive lung disease. While there is some physiologic rationale for a detrimental bronchoconstrictive effect from these agents, the original data supporting this concern is derived from studies conducted in the 1960’s that investigated non-cardioselective beta-blockers (propranolol, oxprenolol, practolol, alprendolol) in both inhaled and oral form on pulmonary function in asthmatic participants[1,2]. In these studies, there was evidence of decreased pulmonary function with these medications; however, many have not been prescribed for any indication in decades, so the applicability of these findings to more modern beta-blocker formulations remains unclear. Furthermore, newer beta-blockers have increased affinity for β1-receptors (cardioselective beta-blockers) which may mitigate the detrimental effects associated with older generation agents. Findings from these early studies using non-selective beta-blockers influenced the recruitment of participants with any obstructive lung disease in subsequent foundational publications that demonstrated the benefit of beta-blockers in the post-myocardial infarction and congestive heart failure (CHF) setting. Exclusion of the COPD population from these landmark studies created uncertainty with clinicians on the proper management of these patients and may have contributed to disproportionate harm in certain subgroups. The suggestion of harm is based on the paradigm that COPD shares many risk factors with cardiovascular disease (CVD) and are at risk for acute myocardial infarction, CHF, and arrhythmias. As a result, many COPD patients are not prescribed beta-blockers even with clear, guideline recommended cardiac indications and numerous studies indicating a lack of harm with utilization of these medications in this population[3–6]. Interestingly, several retrospective analyses of beta-blocker use in COPD patients indicated a mortality benefit and a reduced rate of respiratory exacerbations raising the question of whether these medications may indeed have a therapeutic effect in obstructive lung disease[7–10]. This question culminated into the recently published BLOCK COPD (Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) trial which was designed to evaluate the use of beta-blockers for the treatment of COPD in a population that that did not otherwise have an indication for beta-blocker use[11]. While this trial may inform the use of beta-blockers for the treatment of COPD, practitioners are still left with many questions regarding how to apply the results of this study in conjunction with other published data. In this review, we will synthesize the existing body of data, discuss the pros and cons, and give recommendations on the use of beta-blockers in COPD.

1. Beta receptors in COPD

Beta-adrenergic receptors are located in many tissues in the body including the heart, lung, adipocytes, and pancreas. There are three types of receptors (β1, β2, β3) with higher concentrations of β1 and β2 receptors located in the heart and lung, respectively[12]. The β1-receptors in the heart primarily regulate chronotropy and inotropy. The β2-receptors in the lung activate to decrease the tone of bronchial smooth muscle and subsequently decrease airway resistance. There are a number of genetic polymorphisms associated with different receptor phenotypes that have been shown in cardiovascular disease to alter rates of disease progression as well as response to therapy[13–17]. In COPD, relatively little is known about the role of β-receptor variants in contributing to severity of disease or differential response to beta-agonist therapy. A large Danish cohort study by Thomsen, et al. examined the role of polymorphisms of the ADRB2 gene (Thr164Ile, Gly16Arg and Gln27Glu) which had previously been reported to have the largest effect on β2-receptor function[18]. Utilizing genomic data from almost 9,000 participants in the Copenhagen City Heart Study with over 53,000 participants from the Copenhagen General Population Study used as a validation cohort, the authors found that Thr164Ile heterozygotes had reduced FEV₁ and FEV₁/FVC with a greater risk of COPD as compared to noncarriers. The role of β2-receptor polymorphisms in determining response to drug therapy in COPD has not yet been explored; however, it is certainly plausible that different receptor phenotypes could alter response to beta-agonist therapy and other treatments as well as influence disease progression.

2. Cardiovascular Disease and COPD:

Multimorbidity occurs more commonly in the COPD population and confers an increased risk of mortality [19,20]. Among the most detrimental of these comorbid conditions is cardiovascular disease; however, guidance on screening and treatment of coexisting illness in COPD is lacking. COPD is known to promote a persistent, low-grade inflammatory state that is likely largely driven by smoking and tissue hypoxia[21,22] which has also been implicated in the development of cardiovascular disease[23,24]. Cardiovascular disease (CVD) is an encompassing term that can refer to a number of diseases including ischemic heart disease (IHD), CHF, atrial fibrillation, hypertension, peripheral vascular disease, and cerebrovascular disease.

Cardiovascular disease for the purpose of this review will be restricted to conditions with strong evidence for treatment with beta-blockers including ischemic heart disease, congestive heart failure, and arrhythmia. As current guidelines do not recommend the routine use of beta-blockers for management of hypertension in the absence of IHD or CHF, we will not discuss beta-blocker use for management of hypertension[25]. The prevalence of CVD is high in the COPD population with an estimated prevalence of up to 25% for IHD, 27% for CHF, and 19% for arrhythmia[26,27]. A systematic review and meta-analysis conducted by Chen, et al investigated the association between COPD and CVD using the data from 29 publications[28]. This study found that CVD was more likely to occur in COPD as compared to healthy controls (odds ratio [OR] 2.46; 95% CI 2.02–3.00; p<0.0001). This study further delineated roughly a 2-fold or greater increased odds for specific CVD disorders including ischemic heart disease (OR 2.29; 95% CI 1.76–2.96; p<0.0001), cardiac dysrhythmia (OR 1.94; 95% CI 1.55–2.43; p<0.0001), and CHF (OR 2.57; 95% 1.90–3.47; p<0.0001) in COPD compared to non-COPD. Other than smoking, sedentary lifestyle, and predisposing comorbidities, COPD and CVD have been shown to have several overlapping mechanisms including increased systemic inflammation, thrombotic activity, extracellular matrix degradation, and protease/anti-protease imbalance[29,30]. Despite the preponderance of CVD in COPD patients and its association with worse outcomes, it remains underdiagnosed and inadequately treated with worse mortality than in non-COPD cohorts.

2.1. Ischemic Heart Disease in COPD

Ischemic heart disease encompasses conditions related to sequelae of accumulation of atherosclerotic plaques on the walls of the coronary vessels that obstruct the coronary vessels leading to decreased blood flow in the cardiac muscle and subsequently reduced cardiac function or related to plaque rupture resulting in acute coronary vessel occlusion and myocardial infarction. Studies often use surrogates for IHD including coronary artery disease, myocardial infarction, angina pectoris, and revascularization via coronary artery bypass grafting or percutaneous coronary interventions including angioplasty or stenting. The development of IHD is linked to risk factors including ageing, smoking, and sedentary lifestyle. Some of these risk factors are common to COPD, and data indicate that the risk of death due to IHD increases with declining lung function[31,32]. The common thread between IHD and these other conditions is a persistent low-grade inflammatory state[33]. Cardiac injury occurs frequently in the setting of COPD exacerbations and is associated with higher mortality[34,35]. A secondary analysis of SUMMIT (Study to Understand Mortality and Morbidity Trial) by Kunisaki and colleagues investigated the relationship between CVD events in patients who suffered an acute COPD exacerbation[36]. The original trial sought to answer the question of whether treatment of COPD affects acute cardiac events by enrolling over 16,000 current or former smokers with moderate COPD and carried a diagnosis of CVD which was defined as coronary artery disease, peripheral arterial disease, stroke, myocardial infarction, or diabetes mellitus with resultant organ damage. The results of the analysis, as depicted in Figure 1, determined that the risk of adverse cardiac events in the post-exacerbation setting was increased for up to 1 year with the highest risk being in the first 30 days after the exacerbation event (HR 3.8 [95% CI 2.7–5.5]). The etiology of adverse cardiac events in the peri-exacerbation setting is unclear; however, it is known that circulating inflammatory markers and immune cells are increased in acute exacerbations, and that an increased inflammatory state increases the risk of IHD events potentially through inducing myocardial dysfunction, increasing arterial stiffness, and destabilizing atherosclerotic plaques[37–42]. Beta-blockers improve mortality in the period following an acute cardiac event and are also recommended in the treatment of stable IHD[43]. IHD is independently associated with mortality in the general COPD population accounting for nearly as much mortality as respiratory causes. In a post-hoc analysis of the TORCH (Towards a Revolution in COPD Health) trial by McGarvey, et al., a committee of experts independently adjudicated the cause of death for each patient who died over the course of the study[44]. The records of more than 900 patients were reviewed, and the committee determined IHD to be the cause of death in 26% of patients which was second only to respiratory causes at 35%. Despite the enormous impact of this disease on COPD patients, it remains unrecognized and undertreated. Andell and colleagues examined data from patients admitted to a hospital for an acute coronary syndrome as part of the SWEDEHEART (Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies) cohort to examine the long term outcomes of COPD patients who had suffered a myocardial infarction and evaluate the efficacy of beta-blocker therapy on secondary prevention of cardiovascular events in this population[45]. Patients were longitudinally followed post-discharge for nearly 3 years, and after adjusting for potential confounders using a multivariate model, COPD patients with beta-blocker treatment at discharge showed lower all-cause mortality compared to COPD patients without beta-blocker treatment at the end of the study period (HR 0.87, 95% CI 0.78 to 0.98, P=0.017).

Figure 1.

Risk for cardiovascular disease following an acute exacerbation of COPD. Cardiovascular disease is defined by unstable angina, myocardial infarction, transient ischemic attack, stroke, or cardiovascular death. Data are expressed as hazard ratios (HR) with vertical bars representing 95% confidence intervals (CI) at time points following any COPD exacerbation (left) or COPD exacerbations requiring hospitalization (right). This figure is reproduced with permission from Kunisaki, et al [36].

2.2. Congestive Heart Failure and COPD

CHF occurs when there is reduced forward flow of blood to the systematic circulation from the heart and results from impaired systolic function in the setting of reduced inotropy (systolic failure) or decreased ventricular filling in the setting of impaired ventricular relaxation (diastolic failure). Impaired forward blood flow can cause increased pulmonary vascular pressure manifesting as dyspnea, decreased exercise tolerance, or pulmonary edema even in the setting of normal pulmonary parenchyma. In CHF, there are well-established, guideline-directed therapies which call for the use of angiotensin converting enzyme inhibitors, beta-blockers, diuretics and other medications[46]. In large clinical trials, beta-blockers improve mortality when used for the treatment of CHF[47–49]. The three approved medications are metoprolol succinate, carvedilol, and bisoprolol. As stated previously, CHF is common in COPD patients, and the existence of both diseases is associated with increased mortality[50,51]. COPD may directly impact development of CHF by impairing cardiac filling through mechanisms that include lung hyperinflation and emphysema, particularly in the context of advanced COPD[52–55]. Treatment of CHF in COPD has been shown to reduce morbidity with some indications of improved mortality[56]. In a study by Fisher, et al of nearly 10,000 participants in the Worcester Study Group hospitalized for acutely decompensated CHF were then followed over the course of 10 years[5]. The study confirmed previous data indicating disparate prescribing practices with regard to evidence based CHF treatment, including decreased treatment with beta-blockers in COPD patients compared to non-COPD patients (45.4% vs 59.0%; p<0.001). Furthermore, the authors were able to investigate longitudinally to determine the differences in the disease trajectory of CHF with COPD as a variable of interest. COPD patients admitted for acute decompensated CHF had higher in-hospital mortality (7.9% vs 6.8%; p=0.05), and over the duration of the study survival improved for the non-COPD patients (OR 1.70; 95% CI, 1.23–2.36) but not in patients with COPD (OR, 1.34; 95% CI, 0.92–1.97). Evidence is conclusive that CHF has an increased incidence and prevalence in COPD, and that when identified is less effectively treated with a negative impact on mortality.

2.3. Arrhythmias and COPD

Cardiac arrhythmias are transmission abnormalities in the cardiac conduction system that often result from ischemia or structural heart defects in response to acute injury or longstanding insults from chronic diseases, such as hypertension, lung disease, etc. Atrial tachyarrhythmias, such as multifocal atrial tachycardia, atrial fibrillation, and atrial flutter occur commonly in COPD [57,58] and are seen more frequently as severity of COPD increases[59]. The reasons for this are not completely clear; however, increased sympathetic activity and beta-agonist therapy may play a role[60,61]. Data suggest that atrial abnormalities on electrocardiogram are associated with an increased risk of COPD exacerbation[62,63]. The diagnosis of paroxysmal atrial arrhythmias remains challenging despite association with poor prognosis and progression to sustained tachyarrhythmia[64,65]. There are no recommended screening criteria for arrhythmias in COPD. Treatment is comprised of several classes of medications including rate controlling medications such as non-dihydropyridine calcium channel blockers and beta-blockers as well as rhythm controlling agents, such as amiodarone. Guidelines advise consideration of obstructive lung disease when evaluating for treatment; however, recommendations on specific therapeutic agents are not included, and beta-blockers are not contraindicated[66].

3. Beta-blockers as a Therapy for COPD

The present pharmacologic treatments for COPD are largely relegated to medications designed to alleviate respiratory symptoms and decrease the risk of acute exacerbations. However, with the knowledge that non-respiratory comorbidities drive much of the morbidity and mortality in COPD, it makes sense to target these conditions for therapeutic intervention. The impact of cardiovascular events and cardiac dysfunction in COPD in periods of clinical stability and during acute exacerbations are clear. Beta-blockers are recommended in the treatment of IHD, CHF, and arrhythmias with well-established studies demonstrating reductions in mortality. In COPD, beta-blockers may have additional benefits through augmentation of chronotropic responses in COPD, mitigation of CVD risk, and influencing dynamic hyperinflation. Individuals with COPD have been noted to have higher resting heart rates than those without COPD [67,68]. Resting heart rate has been independently associated with increased mortality in COPD patients [69] which further suggests the use of beta-blockers may be a strategy for therapeutic intervention. Given that inflammation is a potential driver of cardiovascular disease development in COPD and the impact of cardiovascular events on the mortality of COPD patients, it is plausible to hypothesize employing beta-blockers in the treatment of COPD patients may be beneficial. Additionally, evidence suggests beta-blockers may exert positive effects on several other components of respiratory morbidity in COPD including mucous production, oxidative stress, and responsiveness to inhaled beta-agonist therapy via upregulation of beta-receptors in the setting of beta-blocker therapy[70–73].

4. Insights from BLOCK COPD

The BLOCK COPD (Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease) trial was a Department of Defense sponsored, multicenter, randomized, double-blind, placebo-controlled trial evaluating the effect of metoprolol succinate on acute exacerbations of COPD. The trial enrolled 532 participants with at least moderate COPD as defined by a forced expiratory volume (FEV1) to functional vital capacity (FVC) ratio of less than 0.7 and a FEV1 less than 80% predicted. The trial was enriched for an exacerbation-prone COPD phenotype; the enrollment criteria recruited participants who had at least one exacerbation in the prior year as defined by receipt of antibiotics and steroids or a new prescription for supplemental oxygen. Key exclusion criteria were absence of an evidence proven indication for a beta-blocker which was defined as coronary revascularization within the past 3 years or congestive heart failure with a left ventricular ejection fraction less than 40%. The cohorts were well-matched demographically with a mean age of 65 years old and 46% female sex. Interestingly, 15% of participants had a history of coronary artery disease across both groups, consistent with previous observations[28]. The mean FEV1 was 40%, and participants had similar symptom burden and use of supplemental oxygen. The primary endpoint of the trial was time to first COPD exacerbation of any severity. Participants were followed for approximately a year with scheduled interim analyses every six months. At the second interim analysis, the trial was stopped due to an increased frequency of severe exacerbations requiring hospitalization and very severe exacerbations requiring mechanical ventilation in the metoprolol treatment arm. There was also a trend towards increased mortality in the intervention group though this did not reach statistical significance. A summary of the results of BLOCK COPD are shown in Figure 2. Analysis of the subgroup that exacerbated was particularly interesting. This group was largely comprised of older males with moderate COPD (FEV1>40% predicted) who were ex-smokers without a history of severe exacerbations requiring hospitalization. The lack of therapeutic benefit with beta-blockers in a general COPD population was clearly demonstrated in BLOCK COPD; however, the mechanism behind this deleterious effect is unclear. Despite an increased frequency of respiratory events, the difference in change from baseline FEV1 percent predicted to study end was not significantly different between the metoprolol and control groups (−0.78; 95% CI −2.25 – 0.69 percent predicted). Several potential hypotheses have been proposed and are being further investigated including a lack of an ability to mount a chronotropic response in the setting of respiratory compromise, increased air trapping resulting from a decreased response to beta-agonist medication, and lack of utilization of bronchodilator response as an exclusion criteria which has been shown previously to have a more exaggerated decrease in respiratory function with beta-blockade in asthmatic patients. Nevertheless, clinicians must now determine how to apply the results of this trial to their practice, and while numerous observational studies have indicated beta-blockers were safe in COPD patients, the results from BLOCK-COPD may again draw that conclusion into question. This concern is particularly valid in what would be considered “softer” indications for utilization of beta-blockers wherein a demonstrated mortality benefit has not been previously shown (essential hypertension, migraine prophylaxis, etc). There are several studies ongoing that will attempt to further elucidate the role of beta-blockers in the management of COPD by evaluating the effect of both selective and non-selective beta-blockers on airway resistance (NCT01656005) and dynamic hyperinflation (NCT02380053). Of particular interest will be a multicenter, randomized, double-blind, placebo-controlled trial being conducted by investigators in Australia and New Zealand (NCT03917914) which examines the effect of bisoprolol on acute respiratory and cardiac events in a moderate to severe COPD cohort.

Figure 2.

Summary of Exacerbation and Mortality Endpoints from the Metoprolol for Prevention of Acute Exacerbations of COPD (BLOCK-COPD) Study [11]. A) Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time-to-event and mortality; and B) adjusted rate ratio (with 95% CI) for exacerbation risk for metoprolol compared with placebo in the BLOCK-COPD study.

5. Five Year View

The most recent GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines recommend evaluation and treatment of comorbid conditions in COPD with the recognition that they drive a significant portion of cost, morbidity, and mortality; however, clarification on mechanisms of screening for comorbid conditions (echocardiography, cardiac stress testing, arrhythmia monitoring) is lacking[74]. Computed tomography (CT) imaging of the chest is now recommended as part of the guidelines for lung cancer screening which encompasses a large portion of patients with COPD[75]. Additionally, there is a movement towards utilizing CT to quantify emphysema and aid in the diagnosis of COPD[76]. It is conceivable that the increased utilization of these advanced imaging techniques could be used to identify concomitant CVD as well. Bhatt, et al utilized clinical data and non-gated chest CT scans from the COPDGene cohort to screen for ischemic heart disease by assessing for coronary artery calcification (CAC)[77]. The authors concluded that CT imaging and CAC can reliably detect IHD and that presence of CAC is associated with an increased risk of incident IHD over the study period as well as acute cardiovascular events. Evaluation of ventricular dysfunction via non-gated, CT imaging has also been demonstrated as feasible in smokers and could be utilized to screen for concomitant heart failure which may benefit from initiation of appropriate guideline-directed therapy[78]. Another study by Bhatt, et al reviewing clinical and imaging data from more than 3,000 participants from the COPDGene cohort demonstrated that cardiac geometry as determined on non-contrast CT scans can be used to predict reduction in exacerbation frequency associated with beta-blocker use[79]. Whether or not treatment of cardiovascular disease as diagnosed by these modalities would lead to improved outcomes is unclear, but ongoing research into this question is needed.

6. Expert Commentary

A major lesson learned from the BLOCK-COPD trial is that it is of paramount importance to investigate efficacy through well-conducted, randomized-controlled trials and not rely solely on observational studies for clinical decision-making. We can be certain that metoprolol should not be used for the purpose of reducing COPD exacerbation risk in COPD patients with moderate-to-severe airflow obstruction at high risk for COPD exacerbation who do not have an absolute indication for beta-blocker use. However, beta-blockers continue to be underutilized even when they have been shown to be efficacious. For COPD patients with IHD, CHF, or arrhythmias that require beta-blocker use, we recommend using cardioselective agents. Use of non-cardioselective agents should be avoided or used with extreme care. BLOCK-COPD does leave us with additional unanswered questions, including “do other cardioselective beta-blockers (i.e. bisoprolol) have the same influence on exacerbation risk that was observed with metoprolol?”, “do beta-blockers including metoprolol reduce risk for COPD exacerbations among individuals that have an indication for beta-blocker use?”, and “would focusing on chronotropic effects by targeting certain heart rates benefit individuals with COPD?”. These questions, among many others, are areas that warrant further study in a prospective, randomized manner. Recent advances in the use of thoracic computed tomography (CT) to phenotype cardiovascular disease as well as COPD may provide insights about subgroups of individuals with COPD-CVD overlap that may uniquely benefit from beta-blocker therapy.

Article Highlights:

• Review of beta-receptor physiology

• Overview of COPD and Cardiovascular Disease

• Discussion of BLOCK-COPD

• 5-year View of the Field

• Expert Opinion

Key Issues.

• Recognition and management of comorbidities in COPD is of paramount importance.

• Beta-blockers are underutilized in COPD patients that have other indications for use including congestive heart failure, ischemic heart disease, and arrhythmias.

• Cardioselective beta-blockers are preferable over non-cardioselective agents for use in COPD

• Chronic use of metoprolol should not be used as a COPD exacerbation risk reduction strategy in patients with COPD at high risk for exacerbation.