Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events, including cardiovascular mortality. Tiotropium Respimat is associated with a statistically significant increased risk of mortality (RR 1.52; 95% CI 1.06 to 2.16) and cardiovascular death (RR 2.05; 95% CI 1.06 to 3.99) compared with placebo in a meta-analysis of clinical trials. In the largest study, the subgroup of patients with COPD in the Respimat group with known rhythm and cardiac disorders at baseline had an especially high risk for cardiac death (RR 8.6; 95% CI 1.1 to 67.2). Although there was no significantly increased risk of mortality (HR 0.89; 95% CI 0.79 to 1.02) or myocardial infarction (MI) (RR 0.73; 95% CI 0.53 to 1.00) with tiotropium handihaler in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, the reported excess of angina (RR 1.44; 95% CI 0.91 to 2.26), imbalance in strokes related to ischaemia and rates of supraventricular tachyarrhythmias are consistent with the pro-ischemic and pro-arrhythmic effects. The subjects at greatest risk of cardiovascular death, such as those with a recent history of MI, unstable or life-threatening cardiac arrhythmias or hospitalisation with heart failure, were excluded from the UPLIFT trial. The Prevention of Exacerbations with Tiotropium in COPD trial showed an excess of serious coronary ischaemic events of angina, myocardial ischaemia and MI with the tiotropium Handihaler compared with salmeterol. The authors urge caution in prescribing inhaled anticholinergics for patients with preexisting arrhythmias or cardiac disorders. INTRODUCTION Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the USA, and the majority of these deaths are from cardiovascular causes. Since more than 80% of patients with COPD are cigarette smokers, they have a high prevalence of coronary artery disease. In addition, patients with COPD are generally older and the prevalence of undetected arrhythmias is substantial. A reduction in symptoms, primarily dyspnoea, and COPD exacerbations are the potential benefits of inhaled bronchodilators, including shortacting ipratropium bromide and long-acting tiotropium bromide, delivered as a dry powder (Spiriva Handihaler, Boehringer Ingelheim, Inc, Bracknell, UK) or via the new mist inhaler (Spiriva Respimat, Boehringer Ingelheim, Inc). These inhalers have not been demonstrated to alter the progressive decline in lung function or consistently improve survival in COPD. Despite its quaternary ammonium structure which limits diffusion, tiotropium is systemically absorbed as demonstrated by more than 10-fold increased risk of acute urinary retention, especially in older men. Ipratropium and tiotropium are actively transported through the bronchial epithelium using an organic cationic transporter (OCTN2), also present in the human heart. There is preliminary evidence that ipratropium may induce myocardial injury via mitochondrial dysfunction. 7 Pro-arrhythmic effects Anticholinergic drugs suppress parasympathetic control of heart rate which is associated with an increased incidence of tachyarrhythmias and myocardial ischaemia. Although tachyarrhythmias are often considered benign, they confer an increased risk of embolic strokes and sudden death in susceptible cardiac patients. At the time of regulatory approval, tiotropium was known to be associated with mild decreased heart rate variability, which is a known risk factor for cardiac mortality and sudden cardiac death. The Lung Health Study investigators reported a RR for hospitalisations due to supraventricular tachycardia of 4.5 (95% CI 0.97 to 20.8) associated with use of short-acting inhaled ipratropium versus placebo. The accurate prevalence of tachyarrhythmias in randomised controlled trials (RCTs) of tiotropium has not been reliably ascertained because 24 h Holter ECG monitoring was conducted in only a few small studies, 14 and resting 12-lead ECGs performed during clinic visits rarely detect them. However, despite these limitations, an increased risk of arrhythmias associated with tiotropium has been consistently reported in many clinical trials of both formulations. 15e17 Furthermore, the large RCTs of ipratropium and tiotropium have shown a trend towards an increased risk of arrhythmias in comparison with placebo and other bronchodilator drugs. For example, the Understanding Potential Long-Term Impact of Tiotropium on Lung Function Trial (UPLIFT), a large 4-year study of the efficacy of the Spiriva Handihaler, reported relative risks of tachyarrhythmias of 3.70 (95% CI 0.79 to 17.4) and atrial tachycardias of 7.39 (95% CI 0.92 to 59) reported as adverse events. In a recent analysis of three placebo-controlled RCTs from the indacaterol development programme of patients who completed 24 h Holter ECG monitoring those randomised to tiotropium Handihaler had a RR of < An additional table is published online only. To view this file please visit the journal online (http://dx.doi.org/10. 1136/thoraxjnl-2011-201275/ content/early/recent). Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Norwich Medical School, University of East Anglia, Norwich, UK College of Public Health, University of Arizona, Tucson, Arizona, USA Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA Correspondence to Dr Sonal Singh, Department of Medicine, 624 N Broadway, St 680 B and Baltimore, MD, 21205-1901 USA; [email protected] Received 24 October 2011 Accepted 7 June 2012 Singh S, Loke YK, Enright P, et al. Thorax (2012). doi:10.1136/thoraxjnl-2011-201275 1 of 3 Chest clinic C h e st c li n ic Thorax Online First, published on July 4, 2012 as 10.1136/thoraxjnl-2011-201275 Copyright Article author (or their employer) 2012. 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