Authors: Meng-Ting Wang, Jyun-Heng Lai, Chen-Liang Tsai, Jun-Ting Liou
Categories: Review Article, Adverse cardiovascular events, Chronic obstructive pulmonary disease, Drug safety, Inhaled long-acting bronchodilators
Source: Journal of Food and Drug Analysis
Authors: Meng-Ting Wang, Jyun-Heng Lai, Chen-Liang Tsai, Jun-Ting Liou
Inhaled long-acting bronchodilators, including long-acting β2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapy in the treatment of chronic obstructive pulmonary disease (COPD), a disease that poses a heavy burden on morbidity and mortality worldwide. Use of LABAs and LAMAs in patients with COPD, however, has been concerned about an increased risk of adverse cardiovascular events, despite inconsistent findings reported from randomized controlled trials (RCTs) and observational studies. In this review, we detailed the relevant evidence generated from RCTs and observational studies with respect to the risk of cardiovascular disease with use of LABAs and LAMAs in management of COPD, and analyzed the contradictory findings in the literature, as well as recommended future research directions to clear the air regarding the cardiovascular safety of inhaled long-acting bronchodilators.
Chronic obstructive pulmonary disease (COPD) is a common, preventable and irreversible progressive airway obstructive disease, which usually results from a significant exposure to noxious particles or gases. This disease is characterized with persistent respiratory syndromes and exacerbations as well as progressive pulmonary function decline [1,2]. COPD imposes a significant burden to health; It has been linked with multiple comorbid conditions [3] and remains a major cause of death [4]. Specifically, a total of 3.2 million people died from COPD in 2015 worldwide [4].
Inhaled long-acting bronchodilators, including long-acting β2 agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), are the mainstay therapy for management of COPD [5]. LABAs stimulate the β2- subtype—that are expressed in the airway and lung tissue, and block acetylcholine-medicated bronchoconstriction accordingly [6]. Randomized controlled trials (RCTs) have reported that COPD patients receiving LABA or LAMA therapies have a reduced risk of COPD exacerbation, decreased number of COPD hospitalization, and improved health-related quality of life [7,8]. LABA and LAMA therapy are the most central to the symptomatic management of COPD. The newest treatment guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) have suggested that LABA or LAMA therapy can be considered in Group A patients (low symptoms/low risk of exacerbation), and should be initiated in Group B patients (high symptoms/low risk) [9]. Initiation of LAMA monotherapy is recommended in Group C patients (low symptoms/high risk), and an add-on LABA to the LAMA therapy is a preferred treatment for this group of patients with further exacerbations [9]. Additionally, starting therapy with a LABA/LAMA dual therapy is suggested as the initial therapy for the most severe COPD patients, classified as group D patients (high symptoms/high risk) [9].adrenergic receptors located in airway smooth muscles and relax the smooth muscle of airways; LAMAs bind to muscarinic receptors—predominantly the M3
Despite the pivotal role of LABAs and LAMAs for management of COPD, concerns have been raised that exposure to LABAs and LAMAs may lead to adverse cardiovascular events [6]. There is biological plausibility of adverse cardiovascular events from use of LABAs and LAMAs: the pharmacological effects of LABAs and LAMAs are found to exert beyond the site of pulmonary, especially in the heart [10,11]. Although multiple observational studies have revealed an increased risk of adverse cardiovascular events from LABA and LAMA use [12–16], clinical trials have reported contradictory results [17–19]. Therefore, the objectives of this review were to discuss the biological plausibility of the adverse cardiovascular risk with LABA and LAMA therapy first, and then to examine the relevant randomized trials and observational studies for identifying possible reasons that may explain the discrepant findings between RCTs and observational studies, which can serve as a strong basis for designing future studies to clear the air regarding the cardiovascular risk with the inhalation therapy in COPD.
The stimulation of β2-adrenoreceptors (β2-ARs) by LABAs outside the lung is a possible cause of the adverse cardiovascular events associated with the inhaled therapy [10]. β1- adrenoreceptors and β2-ARs coexist in an approximate ratio of 3 and 1 in atria and ventricles, respectively [20]. The presence of β2-ARs is also found in adrenergic nerve terminals in human heart, which facilitates the release of norepinephrine [21]. Through stimulation of β2-ARs, LABAs can accordingly cause positive inotropic and chronotropic responses, resulting in an increased heart rate and myocardial oxygen demand, and direct myocardial injury, which could consequently cause adverse cardiovascular events, such as tachycardia and myocardial infarction [10,22]. Additionally, peripheral vasodilation could also be induced with the stimulation of β2-ARs, and therefore lead to reflex tachycardia [10]. Furthermore, inhaled β2 agonists could also lower plasma K^+^ levels by simulating the Na^+^, K^+^-ATPase coupled to β2-ARs in skeletal muscles, which pumps extracellular potassium ions into the cell, thereby causing hypokalemia that has been associated with ventricular tachycardia and fibrillation [23].
The potential cardiovascular risk of LAMAs is generally considered to result from the suppression of the parasympathetic activity in the heart via antagonism at cardiac muscarinic receptors [11]. These receptors are predominated by M2-muscarinic receptors (M2-receptors) [24], stimulation of which elicits a negative chronotropic and inotropic response in the vagal control of the heart. Use of atropine, amuscarinic antagonist, has been found to increase tachycardia from suppressing the vagal effect of M2-receptors of the sinoatrial nodal pacemaker in an in vivo study [25]. Given most LAMAs have the affinity on M2-receptors, it is suggested that LAMAs could antagonize the subtype of the muscarinic receptors in the human heart, potentially inducing heart rate and tachycardia [11].
Activation of M3 receptors in the heart is also considered to play an important role in regulating and maintaining cardiac function [26], which could be inhibited with use of LAMAs. Stimulation of M3 receptors protects the heart from ischemic injuries by activating antiapoptotic signaling substances, enhancing endogenous antioxidant levels, and decreasing intracellular Ca^2+^ overload [27], as well as stimulates a M3 receptor-activated delayed rectifying K^+^ current, which exerts negative chronotropic responses and antidysrhythmic activity [28]. On the other hand, the beneficial effects from stimulation of M3 receptors are counter-acted by 4-diphenylacetoxy -N-methylpiperidine methiodide (4-DAMP), an M3 selective antagonist [27]. Therefore, it is suspected that potential adverse cardiovascular events associated with LAMAs may also be attributable to antagonizing the M3-receptor-mediated cardiac functions [11].
Randomized trials employ the most rigorous design to maintain a high level of causality due to the adoption of random allocation and blinding, both of which minimize confounding and bias [29]. Accordingly, RCTs are expected to generate findings with a higher internal validity compared with those from other study designs, and provide the strongest evidence of whether use of inhaled long-acting bronchodilators causes an excess risk of adverse cardiovascular events in patients with COPD. However, randomized trials are not entirely free of study limitations. For example, patients enrolled in RCTs are typically highly selected with strict exclusion criteria, resulting in limited external validity to real-world application [29]. Specifically, it has been reported that less than 20% of COPD patients in real-life settings would meet the selection criteria commonly adopted in COPD RCTs [30], and patients participating in large clinical trials had worse lung function and poorer quality of life than those identified from primary care settings [31].
Table 1 describes relevant RCTs reporting cardiovascular end points among patients with COPD receiving either LABA or LAMA monotherapy versus placebo. These trials generally enrolled moderate-to-severe COPD patients, had a differential duration of follow-up, ranging from 6 weeks to 52 weeks, and investigated the individual LABA salmeterol [17], formoterol [32,33], indacaterol [33–35], olodaterol [32] and vilanterol [19] and individual LAMA tiotropium [18,34], aclidinium [36] and glycopyrronium [37]. Spirometry-based lung function measurements [18,32–40] and all-cause mortality [17,19] were the primary outcomes of interest, and cardiovascular events were all measured as a secondary outcome among these trials [17–19,32–41].
Up to till now, all pivotal large RCTs have reported no excess risk of cardiovascular disease (CVD) from use of LABAs and LAMAs as a monotherapy in treatment of COPD [17–19]. The TOwards a Revolution in COPD Health (TORCH) study employed a 3-year randomized and double-blind trial design, and revealed no increased rates of self-reported cardiac disorders for salmeterol used alone (0.114 events per year) or in combination with fluticasone propionate (0.087 events per year) as compared with placebo (0.113 events per year) among 6184 moderate to severe COPD patients [17]. Approximately 40% of patients enrolled in the TORCH trial, however, ever used LABA with or without inhaled corticosteroid at baseline, among whom the cardiovascular adverse events from an initiation therapy of LABA, if any, could not be observed during follow-up. The Study to Understand Mortality and MorbidITy (SUMMIT) [19] study was a double-blind, placebo controlled trial of 16,000 moderate COPD patients with a history or at increased risk of cardiovascular disorder, who were randomly allocated to receive either the once daily inhaled LABA vilanterol 25 μg, inhaled corticosteroid fluticasone 100 μg, vilanterol/fluticasone 25/100 μg combination, or inhaled placebo. In this trial, use of vilanterol alone (hazard ratio [HR] 0.99; 95% CI 0.80–1.22) or in combination with fluticasone (HR 0.93; 95% CI 0.75–1.14) did not increase the risk of the cardiovascular composite endpoint as compared to placebo [19]. Patients were allowed to use other COPD medications for exacerbation during follow-up, including tiotropium, in the SUMMIT trial; nevertheless, the impact of the additional use of other COPD medications on the cardiovascular safety findings was not assessed. The 4-year Understanding Potential Long-term Impact on Function with Tiotropium (UPLIFT) randomized, double-blind trial concluded a lower risk of cardiovascular events (relative risk [RR] 0.84; 95% CI 0.73–0.98) with use of 18 μg tiotropium versus placebo in approximately 6000 moderate-to-very-severe COPD patients [18]. The UPLIFT trial, however, excluded patients with recent cardiovascular disorders, and lacked monitoring whether adverse events occurred for more than 40% of the patients who discontinued the trial. Other individual LABA and LAMA agents, such as indacaterol [33–35], olodaterol [32], aclidinium [36], and glycopyrronium [37] have also been shown not to increase the risk of adverse cardiovascular disease in patients with COPD, despite the inherent study limitations such as few cardiovascular events and exclusion of patients with history of cardiovascular disease.
LABA and LAMA both exert airway bronchodilation through distinct pharmacological mechanisms, and LABA-LAMA combinations are expected to have an efficacy benefit in COPD patients, which have been examined in RCTs along with assessment of adverse cardiovascular effects, including cardiovascular outcomes. Table 1 also details relevant clinical trials assessing the impact of a LABA/LAMA combination therapy on the risk of CVD among COPD patients. A 52-week, randomized, double-blind FLAME trial of 1680 COPD patients revealed that use of the LABA indacaterol 110 μg plus the LAMA glycopyrronium 50 μg yielded similar fatal cardiac events compared to use of the LABA salmeterol 50 μg plus inhaled corticosteroid fluticasone 500 μg (9 versus 11 events), although the fatal events were quite small [41]. Martinez et al. conducted two RCTs of 2103 and 1615 moderate-to-very severe COPD patients, respectively, and reported that patients randomly allocated to glycopyrrolate/formoterol 18/9.6 μg had a similar incidence rate of CVD compared to those receiving glycopyrrolate or formoterol monotherapy or placebo, despite few reported cardiovascular events [42]. Use of olodaterol-tiotropium 5/5 μg versus tiotropium 5 μg once daily for management of moderate-to-severe COPD was not found to increase major adverse cardiovascular events (2% versus 2%) in a 52-week, randomized, double-blind, active-controlled trial, whereas more than 90% of patients were already receiving medication regimens including LABAs or LAMAs at baseline [43]. The InforMing the PAthway of COPD Treatment (IMPACT) study was a randomized, double-blind, multicenter trial of 10,355 patients with COPD, who were randomly allocated to receive 52 weeks of a once daily triple therapy of fluticasone/umeclidinium/vilanterol 100/62.5/25 μg, a dual therapy of fluticasone/vilanterol 100/62.5 μg, or a dual combination of umeclidinium/vilanterol 62.5/25 μg. No clinically relevant differences in electrocardiographic (ECG) measurements were observed among the treatment groups, nor were differences found in the proportion of patients encountering cardiovascular events among the three inhalation regimens (triple 11%; fluticasone-vilanterol: 10%; umeclidinium-vilanterol: 11%). However, approximately 70% of the patients enrolled in the IMPACT trial had received either LABA or LAMA on trial entry, and patients with severe cardiac disease or abnormal 12-lead ECG were excluded at baseline [44]. Other randomized trials examining LABA-LAMA combinations, including umeclidinium/vilanterol 125/25 μg [45,46], tiotropium plus olodaterol 5/5 μg [47], aclidinium plus formoterol 400/12 μg [40], and extrafine beclometasone/formoterol/glycopyrronium 100/6/12.5 μg [48,49] were not found to increase the cardiovascular risk relative to the comparative arm.
There exist several possible reasons for observing no increased risk of cardiovascular disease from inhaled long-acting bronchodilators for management of COPD in randomized trials. First, all of the trials measured cardiovascular end points as a secondary outcome, and they were not statistically powered for examining adverse cardiovascular events. Second, “depletion of the susceptible” might have confounded the cardiovascular safety findings reported from RCTs. Rates of drug-induced adverse events usually peak during the initial time period of drug use and decrease thereafter with a longer treatment [50]. If that is the case for LABA- and LAMA-associated cardiovascular events, most COPD patients enrolled in randomized trials could have developed tolerability to the adverse cardiac events because the majority of the patients included in trials were not LABA-naïve or LAMA-naïve patients. Third, most RCTs excluded patients with a history of cardiovascular disease, a comorbidity highly coexisting with COPD, which may exclude a subgroup of patients at high risk for adverse cardiovascular events. For instance, patients with a history of cardiac arrhythmias, myocardial infarction, or heart failure were excluded from the UPLIFT. Fourth, the impact of additional use of other COPD medications during follow-up on adverse cardiovascular events was not addressed. For example, all of the trials allowed patients to receive rescue medications for COPD exacerbation, such as salbutamol, an individual short-acting β2 agonist (SABA), whereas placebo groups were expected to receive more rescue medications than did treatment groups. Given inhaled SABAs have also been tied with an increased risk of CVD [12], the imbalanced use of SABAs between treatment and control groups, if any, may have masked the increased risk of cardiovascular events from the use of LABAs or LAMAs in patients with COPD.
Taken together with the findings from the aforementioned RCTs, use of LABAs and LAMAs does not lead to an excess risk of adverse cardiovascular events in patients with COPD, and several clinical randomized trials have even reported a protective cardiovascular effect with use of either type of inhaled long-acting bronchodilators. These findings provide reassuring evidence of cardiovascular safety from inhaled long-acting bronchodilators in patients with COPD, whilst the aforementioned study limitations need to be acknowledged when interpreting the cardiovascular data from randomized trials.
Observational studies examining cardiovascular safety of inhaled long-acting bronchodilators for management of COPD often generate findings more closely to reflect real-world medical practice, and consequently could provide the safety evidence with high generalizability. Observational studies have examined adverse cardiovascular events as a primary outcome, and usually evaluated cardiovascular safety of LABA and LAMA in a broad population of COPD patients, such as those with various comorbid conditions [13–16,51–53]. Additionally, LABA- or LAMA-naïve patients diagnosed with COPD had also been examined in observational studies [12–16,51–55], among whom the cardiovascular effect with new initiation of LABA or LAMA, if any, could be revealed. By contrast, observational studies are prone to confounding and bias, which poses a threat to the accuracy of the findings generated from this type of study design. Due to lack of random allocation to treatments in observational studies, measured and unmeasured confounders could be imbalanced between comparison groups, and could cause a spurious observed association. Bias could also occur and distort an observed association with adoption of observational study designs. For instance, decisions for prescribing LABA or LAMA in COPD patients are typically based on uncontrolled COPD disease or exacerbations, which may relate to the development of CVD, and the comparison of LABA or LAMA use versus nonuse of the bronchodilators regarding the differences in the cardiovascular risk could accordingly introduce confounding by indication bias.
Table 2 presents characteristics of observational studies reporting that use of LABAs or LAMAs alone or in combination relative to nonuse or LABA or LAMA monotherapy was associated with an elevated risk of adverse cardiovascular events among patients with COPD, ranging from 1.04-fold to 4.55-fold [12–16,53–56]. These studies adopted either a nested case–control design [13–16,54,55] or a cohort design [53,56], and most of which analyzed COPD patients with comorbid conditions, including those with history of CVD [13–16,53].
Starting a LABA or LAMA therapy for management of COPD has been tied to an increased cardiovascular risk in several observational studies [12–16]. An earlier study revealed a 1.67- fold (95% 1.07–2.60) increased risk of myocardial infarction among patients who first filled one inhaled β2 agonist prescription [12], but the study did not single out use of LABA nor confined to COPD patients. In addition, Wilchesky et al. conducted two studies and concluded that current new use of LABA versus nonuse was associated with a 1.47-fold–4.55-fold increased risk of arrhythmic death, while the findings might be subjected to random error and selection bias [13,14]. Gershon et al. conducted a nested case–control study of 190,000 COPD patients aged ≥66 years, and reported that new use of LABA and LAMA was associated with a 1.31-fold (95% CI, 1.12–1.52) and 1.14-fold (95% CI, 1.01–1.28) increased risk of hospital or emergency room admission for CVD, respectively, compared to nonuse [15]. New initiation of therapy was defined as a prescription of LABA or LABA in the 90 days preceding the index/event date and without any prescription-refill records of the samemedication in the year preceding the index/event date. This nested case–control study [15], however, observed unbalanced baseline characteristics between cases and controls, such as prior cardiovascular disease, and dropped more than 50% of eligible cases. A disease risk score (DRS)-matched nested case–control study of 278,000 COPD patients found that new initiation of LABA and LAMA carried an approximately 1.5-fold increased cardiovascular risk, respectively, irrespective of COPD severity and CVD history [16]. This study first revealed that new use and duration of LABA and LAMA both acted as an important effect modifier of the therapy-related adverse cardiovascular effect in COPD patients [16]. Specifically, the authors discovered that the cardiovascular risk peaked during the 30^th^ day after new initiation of LABA or LAMA therapy, attenuated for 31 days to 60 days of therapies, and reversed to a reduced risk with 71–240 days of use [16]. Confounding was addressed in the study with use of a DRS-matched approach, which balanced all measured factors between cases and controls at cohort entry; nevertheless, residual confounding could not be completely ruled out because several confounders measured preceding the index/event date remained imbalanced between the two comparison groups, although for which statistical adjustment was performed [16]. In addition, the similar findings were reached with adoption of an active comparison with new use of theophylline, an oral bronchodilator in COPD [16], whereas the concern of confounding by indication bias for the reported data had still been raised [57].
Although timing of LABA and LAMA use was not addressed, additional two observational studies also revealed a 1.04-fold–1.24-fold increased risk of cardiovascular events associated with LABA and LAMA therapy for management of COPD [54,56]. The findings of these reports, however, should be interpreted with the context of potential selection bias and few adverse cardiovascular events.
Two observational studies reported no increased risk of cardiovascular events from LABA and LAMA therapy for management of COPD as compared with nonuse [51,58]. While discrepancies of the cardiovascular safety findings among observational studies with positive and negative findings may reflect differences in study designs, clinical settings, and patient characteristics, the two reports with null findings observed a small number of cardiovascular events, and therefore the possibility that random error caused the non-significant observations could not be dismissed.
Observational studies have consistently revealed a comparable risk of CVD between LABAs and LAMAs for management of COPD [15,16,51,52,54], although a reduced cardiovascular risk with LABA/LAMA versus LABA plus inhaled corticosteroid combination has been reported [59]. A head-to-head comparison of risk of adverse cardiovascular outcomes between LABA and LAMA, however, serves as a double-edged sword. Comparison of LABA with LAMA or vice versa for adverse cardiovascular outcomes can minimize confounding by indication bias, but even though a comparable cardiovascular effect is observed, it does not ensure that either type of inhaled long-acting bronchodilators is free of the cardiovascular risk.
Although a body of evidence of observational studies has linked use of inhaled long-acting bronchodilator drugs with the risk of CVD, the interpretation of these results needs to be cautious due to the possibility of the presence of bias and confounding. Specifically, several biases such as selection bias and confounding by indication bias may present, and confounders, especially unmeasured confounding, including pulmonary function and smoking status were not well addressed in observational studies. It is uncertain the degree to which the bias and confounding affect the reported positive findings on the cardiovascular safety of LABA and LAMA in these studies.
Collectively, observational studies revealed inconsistent findings regarding cardiovascular safety of inhaled bronchodilator used for treatment of COPD, but provided new insights on the cardiovascular safety issue. Two studies reported null associations, but they could have suffered insufficient statistical power for observing few cardiovascular events. On the other hand, others reported a 1.04-fold–4.55-fold increased risk of CVD from LABA or LAMA use, but inherent study limitations of confounding and bias from these studies need to be acknowledged. If a true association between use of inhaled long-acting bronchodilators and risk of cardiovascular disease does exist, the observational studies have pinpointed out that the risk is particularly most likely to be tied with new use of LABA and LAMA in patients with COPD, especially during the first 30 days of therapy initiation. This finding allows healthcare professionals to set a specific time period for closely monitoring any symptoms of adverse cardiovascular events in COPD patients receiving inhaled long-acting bronchodilators. It should also be emphasized that the positive findings cannot be interpreted as replacement of LABAs and LAMAs with SABAs or short-acting muscarinic antagonists (SAMAs) for management of COPD 1) LABA and LAMA are more effective than SABA and SAMA in management of COPD disease; and 2) SABA and SAMA are also concerned for an increased risk of adverse cardiovascular events.
Future RCTs that exhibit the following attributes are needed to be performed to clear the air. First, large controlled trials should be designed with a sufficient statistical power to examine cardiovascular end points with LABA and LAMA therapies in patients with COPD. Second, it is recommended to enroll patients with diverse characteristics that can reflect COPD patients seen in present clinical settings, such as those with histories of cardiovascular disease and those with mild COPD severity, both of whom were generally severely undersampled in RCTs. Third, it may not be feasible to adopt a randomized trial design for enrolling LABA-naïve and LAMA-naïve patients, but strategies are urgently required to be explored and developed. Fourth, the use of other COPD medications during follow-up indeed needs to be considered when designing RCTs for evaluating the incidence of cardiovascular events as a primary outcome because placebo patients enrolled in clinical trials generally could receive usual COPD medications as they had received before enrollment, and all patients in treatment and placebo arms were typically allowed to use rescue medications for COPD exacerbation, such as salbutamol. This issue on the concomitant use of other COPD medications during follow-up is urgently required to be addressed in RCTs, given that several COPD medications have also been concerned for their potential to exert cardiovascular effects, such as SABAs and SAMAs.
Future observational studies need also to be conducted with improvements to provide robust findings of adverse cardiovascular risk from LABAs and LAMAs in COPD patients. New techniques and approaches to address confounding and bias are strongly needed for future observational studies, such as a high-dimensional propensity score approach and an instrumental variable analysis. Observational studies are recommended to further consider pulmonary function data, comprehensive histories and symptoms of exacerbation, and even health-related quality of life data for a better classification COPD severity and COPD phenotypes. Population-based electronic medical records are also suggested to be utilized for observational studies to be able to directly measure risk factors of cardiovascular disease and its occurrence. Also, given newer individual LABA and LAMA agents begin to emerge into the market, the new agents need to be examined for the cardiovascular safety in the real world.
We reviewed the current evidence of RCTs and observational studies on use of LABA and LAMA in relation to the risk of adverse cardiovascular disease among patients with COPD. The two types of study designs generated inconsistent findings. On one hand, a body of evidence from observational studies supports the possible link between the use of LABA or LAMA for management of COPD and the cardiovascular risk, whereas confounding and bias may not be entirely ruled out for the positive findings. On the other hand, RCTs have not documented an elevated cardiovascular risk with LABA or LAMA therapy in COPD patients, but the null findings may result from insufficient statistical power, exclusion of patients at high risk for cardiovascular disease, and lack of taking additional use of other respiratory medications during follow-up into account. Future RCTs and observational studies with overcoming the mentioned limitations are urgently required to clear the air regarding the cardiovascular safety of the inhalation therapy.