Cardiac Safety Profile of Nebulized Formoterol in Adults with COPD: A 12-Week, Multicenter, Randomized, Double- Blind, Double-Dummy, Placebo- and Active-Controlled Trial

Abstract

Background: Recently, there have been concerns about the tolerability of long-acting ²-agonists, including possible adverse cardiovascular effects—a particular concern in patients with chronic obstructive pulmonary disease (COPD), who are at elevated risk for cardiovascular disease. Objective: The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution. Methods: Cardiac safety was assessed as part of a 12-week, randomized, double-blind, double-dummy, placebo- and active-controlled trial that was conducted at 38 centers across the United States. Male and female patients aged ≥40 years with COPD and without other significant disease were enrolled. After a 4- to 14-day, single-blind placebo run-in period, patients with COPD were randomly assigned to receive formoterol fumarate inhalation solution 20 µg BID via nebulizer (FFIS group), formoterol fumarate 12 µg BID via dry powder inhaler (FA group), or placebo. Cardiac effects—measured by changes in heart rate (HR) and ventricular premature beats; incidence of proarrhythmic events; change in corrected QT (QTc) interval; and incidence of maximum mean change in QTc ≥60 ms—were assessed using 24-hour Holter monitoring at baseline and 12 weeks; 12-lead electrocardiography at screening and weeks 4, 8, and 12; and patient diary cards. Results: A total of 351 patients with COPD were randomized (mean age, 62.8 years; 56.1% male; mean postbronchodilator forced expiratory volume in 1 second, 1.5 L). Holter monitoring found no clinically meaningful effects of FFIS or FA treatment on mean or maximum HR, ventricular premature beats, or inci dence of arrhythmic events compared with placebo. At week 12, mean (SD) changes from baseline in mean HR were -0.6 (10.9), +0.1 (11.6), and -1.4 (9.4) bpm in the FFIS, FA, and placebo groups, respectively. The incidence of mean maximum changes in QTc ≥60 ms at any time during the 12-week treatment period were 1.6%, 1.8%, and 1.8% with FFIS, FA, and placebo, respectively. Treatment-emergent cardiac adverse events (AEs) occurred in 4.1%, 3.5%, and 4.4% of patients in the FFIS, FA, and placebo groups; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group. No deaths or serious cardiac AEs occurred during the treatment period. Conclusion: In this COPD population, no clinically significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution.