Cardiovascular risk peaks 30 days after starting LABA or LAMA therapy in COPD

Long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstays of therapy for chronic obstructive pulmonary disease (COPD). Controversy exists whether inhaled LABAs (e.g., salmeterol, formoterol) or LAMAs (e.g., tiotropium) increase the risk of cardiovascular (CV) events in patients with COPD. Some studies have observed no increased risk, while others have found a 1.1–4.5-fold increased risk. Some of this discrepancy may relate to the fact that previous randomized clinical trials included prior or existing LABA or LAMA users and excluded patients with baseline CV disease. CV events appearing after first-time LABA or LAMA use has not previously been specifically assessed.Now a new study has examined whether new use of LABAs and LAMAs, and the duration of use since initiating these drugs are important determinants of CV events. The case-control study included 284,220 COPD patients newly started on LABA or LAMA therapies from 2007 to 2011, based on health care claims from the Taiwan National Health Insurance Research Database. All patients were at least 40 years old (mean 71.4 years; 68.9% men).COPD patients requiring hospitalization or emergency care visits for coronary artery disease, heart failure, ischemic stroke or arrhythmia were identified and individually matched to four randomly selected controls. Exposure to LABAs or LAMAs was determined in the year preceding the CV event or index date. Data were stratified according to duration since initiation of LABA or LAMA treatment: current (≤ 30 days), recent (31–90 days), past (91–180 days) and remote (> 180 days). The study identified 37,719 COPD patients with CV disease and 146,139 matched controls, and followed these subjects for a mean of 2.0 years.New LABA and LAMA use in COPD (i.e., within 30 days of starting these drugs) was associated with 1.50-fold and 1.52-fold increases in cardiovascular risk, respectively. CV risk peaked at about day 30 after starting LABA or LAMA therapy. The CV risk waned from days 31–60 of therapy, and fell to 9%–12% below the baseline risk from days 71–240.New LABA use vs new LAMA use showed no difference in CV risk. Individual LABA agents, LAMA dosage forms, and concomitant COPD regimens did not affect CV risk. In addition, the risk of CV events with LAMAs or LABAs remained significant regardless of patients’ CV disease history or COPD exacerbations.The investigators conclude that new initiation of LABAs or LAMAs in patients with COPD is associated with an approximate 1.5-fold increased severe cardiovascular risk within the first 30 days of starting therapy, irrespective of prior CV disease status or history of COPD exacerbations. They estimate that one severe CV event requiring hospitalization or emergency care occurred for every 406 new LABA users and 391 new LAMA users during the first 30 days of therapy.The authors note that this study provides the first evidence indicating that new use and duration of LABA or LAMA use are determinants of CV risk in patients with COPD. Their findings of a duration-response association may help explain why previous randomized controlled trials did not find an increased CV risk with LABA or LAMA use, as earlier studies did not examine CV risks soon after initiating LABA or LAMA therapy.The authors hypothesize that a certain subgroup of patients with COPD may be at particular risk of CV events with initial exposure to LABAs or LAMAs because of predisposing factors that amplify sympathetic overactivation or systemic inflammation with inhaled long-acting bronchodilators. They further suggest that COPD patients who do not experience early CV events and continue to use LABAs or LAMAs may show improved systemic inflammation or more stable lung function status, which could reduce their CV risk.ReferenceWang MT, Liou JT, Lin CW, 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. Published online January 2, 2018. doi:10.1001/jamainternmed.2017.7720.

Cardiovascular risk peaks 30 days after starting LABA or LAMA therapy in COPD

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