PURPOSE: Drug-induced cardiovascular problems are of concern in the use of β2-agonist treatment of respiratory disease, although several recent studies have indicated that long-acting β2-agonists (LABAs) may not be associated with an increased risk. Formoterol is a LABA with rapid onset, high β2 selectivity, and extensive history in the treatment of respiratory disease. Formoterol fumarate inhalation solution (FFIS) has been developed for maintenance treatment of COPD. To evaluate the cardiovascular safety of the nebulized formulation of formoterol and compare it to the dry powder formulation, we conducted a placebo-controlled, double-blind, double-dummy study in patients with COPD.
METHODS: Subjects with moderate-to-severe COPD and no significant comorbidities were randomized to receive 20 mcg FFIS by nebulization, 12 mcg formoterol fumarate by dry powder inhaler (FA), or placebo, each given twice daily, for 12 weeks. Cardiovascular safety was assessed with Holter monitoring, 12-lead ECGs, serum potassium levels, cardiovascular adverse events (CVAEs), vital signs, and physical examinations.
RESULTS: 351 subjects (baseline FEV1 44.5% predicted) were enrolled. Holter monitoring revealed no effects of 12 weeks treatment on mean heart rate (FFIS: 79.9 bpm, FA: 80.3 bpm, placebo: 79.4 bpm), maximum heart rate (FFIS: 116.8 bpm, FA: 117.0 bpm, placebo: 115.7 bpm), or median incidence of ventricular premature beats (FFIS: 10, FA: 17, placebo: 16). ECG results were similar; the incidence of QTc prolongation was minimal and non-treatment related. CVAEs and discontinuations for CVAEs were comparable among groups. No deaths or serious CVAEs occurred. Mean serum potassium levels demonstrated a small decline by end of treatment that was comparable across treatments. Only 1 subject (placebo) demonstrated a clinically significant change in serum potassium levels.
CONCLUSION: Treatment with nebulized formoterol twice daily in this 12-week placebo- and active-controlled study was not associated with an increased incidence of cardiovascular events.
CLINICAL IMPLICATIONS: Nebulized formoterol appears to have a cardiac safety profile that will permit maintenance use and provide a well-known treatment alternative for COPD patients who prefer or require nebulization.
DISCLOSURE: Harold Nelson, No Product/Research Disclosure Information; Grant monies (from industry related sources) Dr. Harold S Nelson Disclosure: Grant Monies (from industry related sources, active): Boehringer Ingelheim, Schering-Plough, IVAX, Novartis, MediciNova, Clinical Therapeutics, Wyeth, Sepracor, Altana, Genentech, GenTel; Employee Dey, LP, Dr. Kimberly Denis-Mize and Mike Rinehart are employees of Dey LP; Consultant fee, speaker bureau, advisory committee, etc. Dr. Harold S Nelson Disclosure: Consultant and/or Advisory Committee Member (since Jan 2006): Dey LP, Novartis/Genentech, Dynavax Technologies, Curalogic, Johnson & Johnson, GlaxoSmithKline, Schering-Plough (Integrated Therapeutics Group), Merck, Astellas, Altana Speakers’ Bureau: AstraZeneca, GlaxoSmithKline