A Post Hoc Holter ECG Analysis of Olodaterol and Formoterol in Moderate-to-Very-Severe COPD

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing cardiac arrhythmias and elevated heart rate. A theoretical mechanistic association based on the interaction of long-acting β(2)-agonists (LABAs) with adrenoreceptors in the heart and vasculature is assumed as a potential class-related risk. Therefore, we performed a pooled analysis of Holter electrocardiogram (ECG) data from four 48-week, randomized, double-blind, placebo-controlled, parallel-group, Phase III clinical trials evaluating olodaterol (5 μg or 10 μg) or formoterol (12 µg) versus placebo. METHODS: We analyzed Holter ECG data from a representative subset of 775 patients with Global Initiative for Chronic Obstructive Lung Disease stage 2–4 COPD from four studies (1222.11–14) assessing olodaterol (5 μg and 10 μg) and formoterol (12 µg) versus placebo. RESULTS: No statistically significant (P>0.3) or clinically relevant differences in the shift from baseline of premature supraventricular or ventricular beats were observed among the active treatment and the placebo groups. Minor and transient differences were observed in the adjusted mean heart rate from baseline during treatment in all groups. There was a numerically small but statistically significant increase for formoterol at Week 24, olodaterol 5 μg at Weeks 12 and 40, and olodaterol 10 μg at Week 40 (all less than 3.0 beats per minute). Mean heart rates returned to a statistically non-significant change at Week 48 for all treatment groups. No increase in major adverse cardiovascular events was observed. CONCLUSION: Treatment with olodaterol or formoterol is not associated with arrhythmias or a persistent increase in heart rate as assessed by Holter ECG in patients with COPD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00782210 (1222.11); NCT00782509 (1222.12); NCT00793624 (1222.13); NCT00796653 (1222.14).