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

Background

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).