Association of Cardiovascular Risk with Inhaled Long-Acting Bronchodilators in Patients with COPD

Dema Mohammed, PharmD, Community-University Health Care Center

Background: Inhaled long-acting β2-agonists (LABAs) and long-acting antimuscarinic antagonists (LAMAs) used in the treatment of chronic obstructive pulmonary disease (COPD) have been found to increase the risk for cardiovascular disease (CVD) in some studies while other studies have shown no increased risk. Wang and colleagues sought to investigate the use of LABAs and LAMAs in COPD and association of CVD risk, specifically focusing on new use, duration of therapy, individual agents, and concomitant COPD therapy regimens.

Purpose: To determine whether duration or initiation of LABAs or LAMAs used in the treatment of COPD are significant determinants of increased risk of CVD.

Study Design: This case-control, observational study took place in Taiwan and 284,220 patients with COPD who were 40 years of age or older were included.Data was retrieved over five years, from January 1, 2007 to December 31, 2011, through the National Health Insurance Research Database (NHIRD). This database consists of records of medical and pharmacy claims covered under the universal national health insurance in Taiwan. The study cohort included patients who made two outpatient visits or one inpatient visit for COPD in a single year with record of filling at least one COPD medication. Entry date for the cohort was set at the first COPD outpatient visit or discharge date if inpatient hospitalization. Patients were excluded if they had already received LABA-LAMA therapy or lacked continuous health insurance coverage for the year before cohort entry, as this was a means of data retrieval. To identify CVD cases, inpatient or emergency room (ER) visits were monitored and identified if a primary cardiovascular diagnosis was listed based on ICD-9 codes, including the following: coronary heart disease, cardiac arrhythmia, heart failure, or ischemic stroke. Cases were matched with randomly selected controls and a disease risk score was estimated. Covariates were measured and important considerations were made for the following: baseline CVD, CVD risk factors (hypertension, diabetes, hyperlipidemia), cardiotoxic medications, and COPD severity.

Results: During a mean follow-up of two years, 37,719 of 284,220 LABA-LAMA-naive patients in the study cohort were identified with severe CVD (hospitalization or ER visit linked to CVD diagnosis code).  The mean age was 71.4 years. Current treatment (≤30 days) with a LABA or LAMA was associated with a 1.50-fold (95% CI 1.35-1.67; P<0.001) and 1.52-fold (95% CI 1.28-1.80; P<0.001) increased risk of CVD, respectively. Use of LABAs was not associated with increased CVD risk with recent initiation of therapy (defined as 31-90 days). For past LABA users (91-180 days), a 10% decrease in CVD risk was identified. Among the LABAs, similar CVD risks were found between salmeterol and formoterol. Similar risks were found in various LAMA regimens, including tiotropium alone. The risk of CVD was absent or decreased with >30 days of LABA or LAMA use. Researchers found that the greatest risk of a CVD event occurred around the 30th day after initiation of LABA or LAMA treatment, attributed to a “phenomenon of depletion of susceptibles.” This phenomenon is described as an increased event rate after initial exposure to a medication and a subsequent decreased event rate with longer exposure to the drug.

Conclusions: This study investigated CVD risk in COPD patients naive to LABA-LAMA therapy and is one of the first studies not to exclude patients with baseline CVD, a drawback of previous large RCTs. In summary, newly initiated (<30 days) LABA or LAMA use in patients with COPD was associated with an increased risk of CVD. Due to this increased event rate, providers should be attentive to cardiovascular disease symptoms within 30 days of initiating a LABA or LAMA for patients with COPD.

Key Points: LABA or LAMA treatment in patients with COPD is associated with an approximate 1.5-fold increased risk of CVD within 30 days of new initiation. This risk was similar across the LABA agents studied (salmeterol and formoterol) and tiotropium, the LAMA agent studied. Given the results of this study, health care providers should evaluate CVD risk prior to initiating treatment with a LABA or LAMA.


  1. Wang MT, Liou JT, Wei Lin C, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study. JAMA Intern Med. 2018 Jan 2; Epub ahead of print.