Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease

Abstract

IMPORTANCEThe associations between cardiovascular disease (CVD) and inhaled long-acting β 2 -agonists (LABAs) or long-acting antimuscarinic antagonists (LAMAs) in chronic obstructive pulmonary disease (COPD) are greatly debated. Pivotal and relevant randomized clinical trials included prior LABA or LAMA users and excluded patients with baseline CVD; therefore, cardiovascular events arising from first-time LABA or LAMA use, if any, could not be observed. There is an urgent need to examine whether new use of and duration since initiating LABAs and LAMAs could act as important determinants of cardiovascular events. OBJECTIVE To investigate risk of CVD associated with LABAs and LAMAs, focusing on the initiation and duration of LABA and LAMA therapies. DESIGN, SETTING, AND PARTICIPANTS This nested case-control study included 284 220 LABA-LAMA-naïve patients with COPD at least 40 years old (mean age, 71.4 years; 68.9% men), retrieved from the Taiwan National Health Insurance Research Database for health care claims from 2007 to 2011. EXPOSURE LABA or LAMA use was measured in the year preceding the event or index date, stratified by duration since initiation of LABA or LAMA treatment, new and prevalent users, concomitant COPD medications, and individual agents. MAIN OUTCOMES AND MEASURESCases with inpatient or emergency care visits for coronary artery disease, heart failure, ischemic stroke, or arrhythmia were identified and individually matched to 4 randomly selected controls. Conditional logistic regressions were performed to estimate odds ratios of CVD from LABA and LAMA treatment.RESULTS During a mean follow-up of 2.0 years, 37 719 patients with CVD (mean age, 75.6 years; 71.6% men) and 146 139 matched controls (mean age, 75.2 years; 70.1% men) were identified. New LABA and LAMA use in COPD was associated with a 1.50-fold (95% CI, 1.35-1.67; P < .001) and a 1.52-fold (95% CI, 1.28-1.80; P < .001) increased cardiovascular risk within 30 days of initiation, respectively, whereas the risk was absent, or even reduced with prevalent use. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not differ in the CVD risks. The risk persisted in an alternative case-crossover study and remained across subgroups without CVD history or prior exacerbations.CONCLUSIONS AND RELEVANCE New initiation of LABAs or LAMAs in patients with COPD is associated with an approximate 1.5-fold increased severe cardiovascular risk, irrespective of prior CVD status and history of exacerbations.

Increased risk of major adverse cardiac events following the onset of acute exacerbations of COPD

“…For example, individuals may initiate or intensify use of bronchodilators during an exacerbation . As these drugs stimulate sympathetic control and suppress the parasympathetic nervous system, their use may imply a short‐term increased cardiovascular risk . Similarly, exacerbations are often also treated with antibiotics.…”

“…16 As these drugs stimulate sympathetic control and suppress the parasympathetic nervous system, their use may imply a short-term increased cardiovascular risk. 32,33 Similarly, exacerbations are often also treated with antibiotics. Although some antibiotics may increase the risk of cardiac events, 34,35 it is the site of infection more than the choice of antibiotic causing the increased risk.…”

Chinese herbal medicine reduces the risk of urinary incontinence in patients with chronic obstructive pulmonary disease: A population‐based retrospective cohort study

“…In the pharmacological therapies for COPD and urinary incontinence, adverse effects and drug-drug interactions are also noted, which is consistent with recent studies. 19 As shown in Table S3, COPD patients taking Xiao Qing Long Tang are associated with alleviated airway inflammation and restored airway remodeling, 20 Log-Rank test, P = 0.0009 CHM cohort Fig. 2 Cumulative incidence of urinary incontinence after 10 years for the CHM cohort and non-CHM cohort in patients with COPD.…”

Revefenacin, a Long‐Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo‐ and Positive‐Controlled Thorough QT Study

“…[12][13][14] These patients have a 2 to 5 times elevated risk of ischemic heart disease, cardiac arrhythmia, and heart failure. 14 Some case studies have reported LAMA and long-acting beta agonist (LABA) treatments increase the risks of cardiovascular events in COPD patients 15,16 ; however, other studies, including prospective trials, have shown no elevated risks for cardiovascular events with LAMA or LAMA/LABA combinations. [17][18][19][20] Revefenacin has not been associated with adverse cardiovascular events in 2 identical double-blind, placebo-controlled, 12-week phase 3 trials (NCT02512510, NCT02459080) 21 or in a 52-week double-blind phase 3 study (NCT02518139) 22 of patients with moderate to very severe COPD.…”