Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease: A Nested Case-Control Study

Abstract

Importance: The associations between cardiovascular disease (CVD) and inhaled long-acting β2-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 measures: Cases 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.

Figure 1.. Duration-Response Curves for the Adjusted Odds Ratios (95% CIs) of the Cardiovascular Risk as a Function of Duration of New LABA and New LAMA Therapy

Duration-response curves for the adjusted odds ratios (solid line) and 95% CIs (dashed line) of the cardiovascular risk as a function of duration of new inhaled long-acting β₂-agonists (LABAs) therapy (A) and duration of new inhaled antimuscarinic antagonists (LAMAs) therapy (B) by using a restricted cubic splines function in multiple conditional logistic regressions.

Figure 2.. Sensitivity Analysis of Cardiovascular Disease (CVD) Risk With New Use of LABA and LAMA

COPD indicates chronic obstructive pulmonary disease; OR, odds ratio; SABAs, short-acting β₂-agonists. ^aP < .05. ^bWe confined analysis to patients who had been tested with spirometry for lung function in the 30 days before or on the date of the new prescription of inhaled long-acting β₂-agonists (LABAs) and inhaled antimuscarinic antagonists (LAMAs). ^cThese analyses were measured in the 30 days before the index date.