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Patients With COPD Using Triple Therapy Face Increased Cardiovascular Risk, Study Finds


Patients with chronic obstructive pulmonary disease (COPD) on triple therapy face an increased cardiovascular risk.

Patients with chronic obstructive pulmonary disease (COPD) receiving triple therapy face an increased cardiovascular risk, according to a study published in the International Journal of Chronic Obstructive Pulmonary Disease.

The researchers explained that cardiovascular complications are major causes of death in patients with COPD as they face many related comorbidities, like hypertension, chronic heart failure, and ischemic heart disease. To help treat COPD symptoms, current guidelines recommend patients use inhaled long-acting bronchodilators due to the beneficial effects of long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) documented in several clinical trials. Conversely, concerns have been raised over adverse events in patients with COPD using inhaler therapy—in particular, about cardiovascular complications associated with LAMA and LABA exposure.

The investigators noted that further research was needed in this area, as previous studies reported mixed results. Also, they explained that few studies have examined the development of cardiovascular comorbidities in patients with COPD being treated with new therapeutic inhaler therapy interventions, including the LABA/LAMA/inhaled corticosteroid (ICS) combination, in a real-world setting. Consequently, the researchers investigated the development of new cardiovascular events in patients with COPD due to inhaler treatments and comorbidities.

To do so, the researchers retrospectively analyzed data registered in the Korean Health Insurance Review and Assessment Service (HIRA) database between January 1, 2015, and December 31, 2020. HIRA is an agency that has accumulated all medical reimbursement records in South Korea, which can be used to assess the nationwide impact of an illness and subsequent health care. They analyzed patients aged 40 years or older with International Classification of Disease, Tenth Revision (ICD-10) codes for COPD or emphysema who received inhaler prescriptions 3 or more times during the observation period; the date of the first inhaled respiratory medication prescription was considered the index date.

3D illustration of heart | Image Credit: Siarhei - stock.adobe.com

Patients with chronic obstructive pulmonary disease (COPD) on triple therapy face an increased cardiovascular risk. | Image Credit: Siarhei - stock.adobe.com

They considered cardiovascular outcomes to be when patients made an inpatient or emergency department visit with a primary diagnosis of ischemic heart disease (ICD-10 codes I20-I25), heart failure (I50), myocardial infarction (I21-I22), arrhythmia (I44-I49), atrial fibrillation/flutter (I48), hemorrhagic stroke (I60-I62), or ischemic stroke (I63-I66); the researchers investigated the development of new cardiovascular events as primary outcomes from the index date until December 31, 2020.

The study population consisted of 46,308 patients, 45.9% of whom had hypertension, 23.3% had diabetes mellitus, and 46.7% had a Charlson Comorbidity index score of 3 or greater. The researchers divided the patients into 3 groups: the LAMA/LABA group (n = 28,322), the ICS/LABA group (n = 11,812), and the triple-based (LAMA/ICS/LABA therapy) group (n = 6174). They noted that the triple therapy group had a higher proportion of male patients, older patients, patients with higher Charlson Comorbidity Index scores, and patients with more frequent hospitalizations and emergency room visits during the covariate assessment window (all P < .001).

Through multivariable Cox analyses, the researchers found that compared with ICS/LABA therapy, triple therapy was independently associated with the development of ischemic heart disease (HR, 1.22; 95% CI, 1.04-1.43), arrhythmia (HR, 1.72; 95% CI, 1.41-2.09), heart failure (HR, 1.45; 95% CI, 1.14-1.84), and atrial fibrillation/flutter (HR, 2.31; 95% CI, 1.64-3.25); they noted that LAMA/LABA therapy did not show a significant association.

Also, emergency room visits during the covariate assessment window were independently associated with the development of heart failure, arrhythmia, ischemic heart disease, and atrial fibrillation/flutter (P < .05). Lastly, multivariable analyses found that tuberculosis (HR, 1.43; 95% CI, 1.10-1.85), older age, diffuse interstitial lung disease (HR, 2.00; 95% CI, 1.24-3.24), and hypertension were independently associated with arrhythmia development (all P < .05).

The researchers acknowledged their study’s limitations, one being that they did not measure medication adherence. Additionally, due to the study's observational design, the researchers could not firmly suggest a causal link. Lastly, the researchers did not analyze potential confounders like pulmonary function tests, laboratory tests, and hypercholesterolemia that may contribute to the occurrence of cardiovascular disease because the study was conducted with a claims database. Despite these limitations, they expressed confidence in their findings and suggested areas for future research.

“…our data demonstrated that the development of cardiovascular events in COPD was associated with triple therapy compared to ICS/LBA therapy, suggesting cardiovascular risk should be considered in COPD patients receiving triple therapy,” the authors concluded. “However, further verification is necessary, considering the confounding bias resulting from disparities in each group.”


Kim EK, Lee E, Park JE, et al. Cardiovascular events according to inhaler therapy and comorbidities in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2024;19:243-254. doi:10.2147/COPD.S433583

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