The safety of anticholinergic bronchodilators for the treatment of chronic obstructive pulmonary disease

Introduction: Poorly absorbable quaternary ammonium-inhaled muscarinic antagonists both as the short-acting ipratropium and as long-acting (12 - 24 h) agents (tiotropium, glycopyrronium, aclidinium and umeclidinium) have all demonstrated statistically and clinically significant efficacy in chronic obstructive pulmonary disease compared with placebo. However, controversy has arisen concerning the safety of this class of agents principally regarding their association with both fatal and nonfatal cardiovascular toxicity. Areas covered: The safety of both ipratropium and the long-acting muscarinic antagonists is reviewed with a major emphasis on potential cardiovascular toxicity, based on published clinical trials data and results of analyses of pooled data, meta-analyses, and observational studies. Since glycopyrronium, aclidinium, and umeclidinium have become available only relatively recently, more emphasis will be placed on the more extensive literature concerning the safety of the older anticholinergic compounds, the short-acting ipratropium, and the long-acting tiotropium in its dry powder formulation, as well as its newer soft mist inhaler delivery device. Expert opinion: Pooled analyses and meta-analyses of randomized controlled trials (RCTs) of tiotropium in both its dry powder and soft mist formulations, as well as some observational studies, have implicated this agent as increasing the risk of nonfatal and fatal cardiovascular events. However, the most robust evidence based on large-scale randomized controlled trials (RCTs) of relatively long duration specifically designed to evaluate the cardiovascular safety of tiotropium have not confirmed these safety concerns. Because of the relatively limited amount of safety data for the newer long-acting muscarinic antagonists compared to the far more extensive experience with tiotropium, it will be important to accumulate additional safety information from post-marketing pharmacovigilance for these newer agents.