Major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study

Chronic obstructive pulmonary disease (COPD) is a complex respiratory disorder characterized by chronic airflow limitations and increased inflammatory responses in the airways [1]. Comorbidities are frequent in COPD and significantly affect patient’s quality of life, exacerbation frequency, and survival [1, 2]. The most prevalent comorbidities include cardiovascular disease (hypertension, ischemic heart disease, heart failure), metabolic syndrome (diabetes mellitus, hyperlipidemia), osteoporosis and chronic kidney disease (CKD) [1, 3].

Inhaled bronchodilators, including long-acting β2-agonists (LABA) and long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS) are the cornerstone therapies for COPD patients [1]. The clinical efficacy of inhaled bronchodilators has been demonstrated in clinical trials as quality of life improvement, prevention of lung function decline, and reduction of acute exacerbation frequency. However, several studies have raised concerns that inhaled bronchodilators increase the risk of cardiovascular events [4‐10]. Moreover, renal impairment is also a common comorbidity in elderly COPD patients [11, 12] who may be at higher risk of adverse events due to decreased elimination and increased systemic effects of long-acting bronchodilators [13‐15]. However, in large clinical trials, COPD patients with significant renal impairment or cardiac disease were usually excluded from the studies [16‐18], therefore, the safety issue of COPD patient with significant renal or cardiovascular disease using long-acting bronchodilators is still being debated [9, 10, 15, 16, 19‐21].

A recent analysis showed that COPD patients with CKD had high risk of pre-existing cardiovascular comorbidity [21] and they found that the safety and tolerability of dual bronchodilator is comparable to the monocomponents, irrespective of the level of renal impairment. However, the number of patients with moderate to severe renal impairment at baseline in the study remained low (less than 15%), which may not reflect the conditions in real-life practice. Moreover, the adverse effects and the cause of mortality might not be well documented among COPD patients with major comorbidities using various inhaled medications in real-life care. Here we conducted a case-control study to investigate the association of common inhaled medications, including combining different classes of bronchodilators (LAMA and LABA) and different ICS, and the development of clinically important cardiovascular events and outcomes in COPD patients with major comorbidities.

Our findings demonstrated that comorbid CVD or CKD but not bronchodilator use were independent risk factors for cardiovascular events in COPD patients using long-acting inhaled bronchodilators. In COPD patients with CKD, the risk of adverse cardiovascular events increased 1.02-fold over that of patients with COPD alone for each 1 mL/min decrease in renal creatinine clearance. In COPD patients with both CKD and CVD, this risk enhanced to 6.32-fold over that of those with neither comorbidity, regardless of the type of inhaled long-acting bronchodilator used. Furthermore, we found that CKD was the only independent risk factor to predict cardiovascular-related mortality in COPD patients. This is the first study to raise the possibility that the increased risk of adverse cardiovascular events among COPD patients using inhaled bronchodilators results from CVD and/or CKD as their major comorbidities and history of frequent exacerbations, rather than from the use of inhaled medications themselves.

We observed that COPD patients who used LAMA had a higher risk for cardiovascular events in univariate analysis that was not statistically significant in multivariate analysis. In contrast, prior nested case-control studies by Wang et al. [9] and Gershon et al. [10] found that COPD patients newly prescribed LAMAs or LABAs were at higher risk of cardiovascular events, irrespective of prior CVD status. This discrepancy might attribute that their potential misclassification of patients with COPD by ICD codes in the National Health Insurance Research Database (without lung function confirmation) and the majority COPD patients in the cohort did not receive standard treatment (less than 15% of the patients with COPD who had cardiovascular events had been treated with long-acting bronchodilators, and the most of them used oral theophylline, beta-agonists, and an oral corticosteroid as the initial treatment) [9], which further increased cardiovascular side effects [23, 24].

Many observational studies and meta-analyses have reported that increase cardiovascular risk in patients with COPD was associated with their use of long-acting bronchodilators [5, 19, 20, 25, 26], nevertheless, the randomized controlled trials failed to show an increased risk [16, 27, 28] and a recent study even demonstrated that a LAMA/LABA combination improves cardiac function in COPD patients with lung hyperinflation [29]. This discrepancy may be partially attributable to the fact that most clinical trails have excluded patients with severe or multiple comorbidities. One population-based study indicated that the risk of cardiovascular events after initiation of long-acting bronchodilators is 3.5-fold higher in patients with baseline CVD who are taking CVD medications [30]. Similarly, we also observed that COPD patients with baseline CVD had higher risk of cardiovascular effects than those without, regardless of treatment regimens for COPD. Further multivariate analysis demonstrated that patients with baseline CVD predicted the risk of adverse cardiovascular events. Although inhaled long-acting bronchodilators are recommended as maintenance therapy for stable COPD patients [1], clinicians should be cautious when prescribing these medications to patients with preexisting cardiovascular disease.

Recent studies showed that CKD not only has a significantly higher prevalence in COPD patients than in healthy controls [31‐33], but also an important risk factor for CVD [34], which may carry high risk of cardiovascular complications [35]. The finding is of concern because LABA and LAMA are both excreted in the urine, and the systemic exposure of LABA and LAMA would be higher in COPD patients with renal impairment than those with normal renal function [14, 36]. Thus, COPD patients with CKD receiving long-acting bronchodilators might lead to severe adverse cardiovascular effects after long-term exposure [15] and even lead to significantly higher risk of death compared to those without CKD [37‐39]. Our findings documented that COPD patients comorbid CKD not only have higher risk of cardiovascular events and also predict the risk of cardiovascular-related mortality. However, this data highlights the need for further prospective studies to investigate the underlying mechanisms and potential interventions to improve outcomes in this population.

Comparative studies have failed to show a significant difference in the risk of mortality and serious adverse events between LAMA, LABA, and ICS/LABA [40, 41]. Nevertheless, a systematic review and meta-analysis demonstrated that LAMA use was associated with higher risk of overall and cardiovascular death compared with other inhaled medications and ICS/LABA use was associated with the lowest risk of overall death among all treatments [42]. Differently, our reports showed that COPD patients with CKD, CVD, history of frequent exacerbations and underlying malignancies were associated with high risk of all-cause mortality, and those treated with ICS/LABA were associated with better outcome. These results imply that clinicians should not only foucs on the selection of inhaled bronchodilators for COPD, but also target the extra-pulmonary comorbidities as treatable traits to improve outcomes in real-world practice [43].

Our study has several limitations. First, our study population was extracted from only one medical center database, so the results may not be applicable to patients examined at other clinics. Second, not all the prescriptions of inhaled bronchodilators were regulated by guidelines and the data is based on retrospective chart review. Thus, the COPD treatment may not be standardized and the adherence rate of inhalers could not be assessed. Third, the observed association between cardiovascular events in patients with preexisting cardiovascular conditions and the initiation of inhaled bronchodilators does not imply cause and effect. Fourth, we did not include COPD patients with CVD who are not taking inhaled COPD therapies for further clarifying the effects of inhaled bronchodilators on patients with CVD, which is attributed to very few diagnosed COPD patients without receiving any standard inhaled long-acting bronchodilators, even they with CV comorbidity. Fifth, our cohort enrolled relatively higher percentage of nonsmoker COPD patients (49.1%), which could be explained by enrollment of patients with asthma and COPD overlapped (ACO) and our patients had long-term exposure to highest level of fine particulate matter (PM_2.5) in Taiwan [44]. Sixth, nearly one-fourth of patients (n = 380, 24.3%) had inhaler switching during the follow-up period and were reclassified to different groups after inhaler switch. However, in the real-world data with retrospective nature, we could not avoid the impact of carryover effects without washout periods. Finally, we did not investigate the medications used to treat underlying comorbidities such as DM, hypertension, or hyperlipidemia, or oral drugs for COPD patients.

The risk of cardiovascular events was associated with COPD patients with preexisting CKD or CVD, and history of frequent exacerbations rather than associated with the use of inhaled bronchodilators. Clinicians should closely monitor COPD patients with preexisting CKD and CVD for adverse cardiovascular events while using inhaled long-acting bronchodilators.