Evaluating cardiac safety of tiotropium in patients with COPD: Combined analysis of Holter-ECG data from four trials

Background: Extensive clinical trial data have shown that different doses of tiotropium, administered via either HandiHaler® 18 µg (HH18) or Respimat®, improves lung function, quality of life and reduces exacerbations in patients with chronic obstructive pulmonary disease (COPD); however, there is concern that antimuscarinic agents may induce cardiac arrhythmias in a vulnerable subpopulation of patients with cardiovascular comorbidity. Aims and objectives: To support the cardiac safety of tiotropium maintenance therapy by investigating heart rate and arrhythmia parameters. Methods: Combined analysis of all tiotropium trials (HH18 and/or R1.25 - 10) in COPD involving Holter-electrocardiogram (ECG) monitoring conducted between 2003 and 2012. Men and women aged= 40 years with a smoking history of= 10 pack-years, and a clinical diagnosis of COPD were included. Holter-ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical endpoints were derived for each of the Holter-monitoring days. Results: Four trials (n= 727 patients) were included, ranging from 4 - 48 weeks' treatment duration. Mean age was 64.7 years. Neither R1.25 - 10 nor HH18 were associated with changes in HR, SVPBs, VPBs and pauses compared to placebo or the pretreatment baseline period. There was no evidence of an exposure-effect relationship for the cardiac arrhythmia endpoints. Conclusion: Tiotropium maintenance therapy with R1.25 - 10 or HH18 was well tolerated and not associated with an increased risk of cardiac arrhythmia in patients with COPD in this analysis.