No Influence on Cardiac Arrhythmia or Heart Rate from Long-Term Treatment with Tiotropium/Olodaterol versus Monocomponents by Holter ECG Analysis in Patients with Moderate-to-Very-Severe COPD

Abstract

Stefan Andreas,1,2 Ulrich Bothner,3 Alberto de la Hoz,3 Isabel Kloer,3 Matthias Trampisch,3 Peter Alter4 1Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany; 2LungClinic Immenhausen, Immenhausen, Germany, Member of the German Center for Lung Research (DZL); 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 4Department of Medicine, Pulmonary and Critical Care Medicine, Philipps University of Marburg (UMR), Marburg, Germany, Member of the German Center for Lung Research (DZL)Correspondence: Stefan AndreasDepartment of Cardiology and Pneumology, Robert-Koch-Str. 40., Göttingen, GermanyTel [phone]Fax [phone]Email [email protected]: Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.Methods: We analyzed Holter ECG data from a representative subset of patients (N=506) from the two pooled replicate studies (TONADO 1 and 2) assessing tiotropium/olodaterol 5/5 μg therapy versus tiotropium 5 μg or olodaterol 5 μg monotherapy, inhaled once daily (two single inhalations) using the Respimat® Soft Mist™ inhaler device. Additionally, major adverse cardiac events (MACE) with tiotropium/olodaterol were assessed versus the respective monotherapies.Results: After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 μg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 μg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 μg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 μg (– 0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.Conclusion: Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.Trial Registration: TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).Keywords: tiotropium, olodaterol, Holter ECG, heart rate, arrhythmia, safety

Keywords

• tiotropium
• olodaterol
• holter ecg
• heart rate
• arrhythmia
• safety