Mortality and cardiovascular outcomes associated with medications used in the treatment of chronic obstructive pulmonary disease

Studies have found an increased risk of asthma-related deaths in salmeterol users and an increased risk of cardiovascular morbidity & mortality associated with the use of ipratropium bromide. Our objective was to examine the association of long acting beta2-agonists (LABA) with all-cause mortality and cardiovascular events (CVEs) as well as the association of inhaled anticholinergic agents with CVEs, in Chronic Obstructive Pulmonary Disease (COPD) patients. We performed a cohort study of veterans newly diagnosed with COPD. We used Cox regression to estimate the risk of all-cause mortality and CVEs associated with exposure to LABAs and anticholinergics within the past year, and to adjust for potential confounders. We explored effect-modification by inhaled corticosteroid (ICS) use within the past year, preexisting cardiovascular disease (CVD) and race. The relative risk (RR) of all-cause mortality comparing patients exposed vs. unexposed to LABAs within the past year was 1.07 (95% CI 1.01-1.14). Effect modification by ICS use within the past year was statistically significant (RR (95% CI), ICS users: 1.00 (0.92-1.09) and ICS non-users: 1.14 (1.05-1.24). There was an increased risk of CVEs associated with LABAs in African Americans (RR 1.46, 95% CI 1.09-1.96) and patients without prior CVD (RR 1.33, 95% CI 1.09-1.61). Compared with subjects not exposed to anticholinergics within the past year, any exposure to anticholinergics within the past 6 months was associated with an increased risk of CVE (RR (95% CI) for ≤4 & >4 thirty-day equivalents: 1.40 (1.30-1.51) & 1.23 (1.13-1.36) respectively). Among subjects who received anticholinergics more than 6 months prior, there did not appear to be an elevated risk of CVE. In conclusion, the increased risk of all-cause mortality associated with LABAs was limited to patients who had not used ICS. Clinicians should consider addition of ICS to LABA therapy in COPD patients. Clinicians should be cautious when prescribing LABAs to African Americans and patients without diagnosed CVD. We also found an increased risk of CVEs associated with the use of inhaled anticholinergic medications within the past 6 months. These findings raise concerns about the cardiovascular safety of LABAs and anticholinergic medications.